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Melanoma: HELP
Articles by George F. Murphy
Based on 49 articles published since 2010
(Why 49 articles?)
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Between 2010 and 2020, G. Murphy wrote the following 49 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial A Festschrift for Martin C. Mihm, Jr. 2010

Murphy, George F. · ·J Cutan Pathol · Pubmed #20482668.

ABSTRACT: -- No abstract --

2 Review Epigenetic markers in melanoma. 2015

Guo, Weimin / Xu, Ting / Lee, Jonathan J / Murphy, George F / Lian, Christine G. ·Program in Dermatopathology, Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, 221 Longwood Ave. EBRC 401, Boston, MA 02115, USA. ·Melanoma Manag · Pubmed #30190864.

ABSTRACT: Melanoma, one of the most virulent forms of human malignancy, is the primary cause of mortality from cancers arising from the skin. The prognosis of metastatic melanoma remains dismal despite targeted therapeutic regimens that exploit our growing understanding of cancer immunology and genetic mutations that drive oncogenic cell signaling pathways in cancer. Epigenetic mechanisms, including DNA methylation/demethylation, histone modifications and noncoding RNAs recently have been shown to play critical roles in melanoma pathogenesis. Current evidence indicates that imbalance of DNA methylation and demethylation, dysregulation of histone modification and chromatin remodeling, and altered translational control by noncoding RNAs contribute to melanoma tumorigenesis. Here, we summarize the most recent insights relating to epigenetic markers, focusing on diagnostic potential as well as novel therapeutic approaches for more effective treatment of advanced melanoma.

3 Review Melanoma epigenetics: novel mechanisms, markers, and medicines. 2014

Lee, Jonathan J / Murphy, George F / Lian, Christine G. ·Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ·Lab Invest · Pubmed #24978641.

ABSTRACT: The incidence and mortality rates of cutaneous melanoma continue to increase worldwide, despite the deployment of targeted therapies. Recently, there has been rapid growth and development in our understanding of epigenetic mechanisms and their role in cancer pathobiology. Epigenetics--defined as the processes resulting in heritable changes in gene expression beyond those caused by alterations in the DNA sequence--likely contain the information that encodes for such phenotypic variation between individuals with identical genotypes. By altering the structure of chromatin through covalent modification of DNA bases or histone proteins, or by regulating mRNA translation through non-coding RNAs, the epigenome ultimately determines which genes are expressed and which are kept silent. While our understanding of epigenetic mechanisms is growing at a rapid pace, the field of melanoma epigenomics still remains in its infancy. In this Pathology in Focus, we will briefly review the basics of epigenetics to contextualize and critically examine the existing literature using melanoma as a cancer paradigm. Our understanding of how dysregulated DNA methylation and DNA demethylation/hydroxymethylation, histone modification, and non-coding RNAs affect cancer pathogenesis and melanoma virulence, in particular, provides us with an ever-expanding repertoire of potential diagnostic biomarkers, therapeutic targets, and novel pathogenic mechanisms. The evidence reviewed herein indicates the critical role of epigenetic mechanisms in melanoma pathobiology and provides evidence for future targets in the development of next-generation biomarkers and therapeutics.

4 Review Non-cutaneous melanoma: is there a role for (18)F-FDG PET-CT? 2014

Murphy, G / Hussey, D / Metser, U. ·Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital and Women's College Hospital, University of Toronto, Toronto, ON, Canada. ·Br J Radiol · Pubmed #24901893.

ABSTRACT: Non-cutaneous melanomas (NCM) are diverse and relatively uncommon. They often differ from cutaneous melanomas in their epidemiology, genetic profile and biological behaviour. Despite the growing body of evidence regarding the utility of positron emission tomography (PET)/CT in cutaneous melanoma, the data on its use in NCM are scarce. In this review, we will summarize the existing literature and present cases from our experience with NCM to illustrate current knowledge on the potential role and limitations of fluorine-18 fludeoxyglucose PET/CT in NCM.

5 Review Stem cells and targeted approaches to melanoma cure. 2014

Murphy, George F / Wilson, Brian J / Girouard, Sasha D / Frank, Natasha Y / Frank, Markus H. ·Department of Pathology, Brigham & Women's Hospital, Boston, MA, USA. Electronic address: gmurphy@rics.bwh.harvard.edu. · Transplantation Research Center, Children's Hospital Boston, Boston, MA, USA; Department of Dermatology, Brigham & Women's Hospital, Boston, MA, USA. · Dermatology Residency Program, Harvard Medical School, Boston, MA, USA. · Department of Medicine, VA Boston Healthcare System, Boston, MA, USA. · Transplantation Research Center, Children's Hospital Boston, Boston, MA, USA; Department of Dermatology, Brigham & Women's Hospital, Boston, MA, USA. Electronic address: markus.frank@childrens.harvard.edu. ·Mol Aspects Med · Pubmed #24145241.

ABSTRACT: Melanoma stem cells, also known as malignant melanoma-initiating cells, are identifiable through expression of specific biomarkers such as ABCB5 (ATP-binding cassette, sub-family B (MDR/TAP), member 5), NGFR (nerve growth factor receptor, CD271) and ALDH (aldehyde dehydrogenase), and drive melanoma initiation and progression based on prolonged self-renewal capacity, vasculogenic differentiation and immune evasion. As we will review here, specific roles of these aggressive subpopulations have been documented in tumorigenic growth, metastatic dissemination, therapeutic resistance, and malignant recurrence. Moreover, recent findings have provided pre-clinical proof-of-concept for the potential therapeutic utility of the melanoma stem cell concept. Therefore, melanoma stem cell-directed therapeutic approaches represent promising novel strategies to improve therapy of this arguably most virulent human cancer.

6 Review Progression of cutaneous melanoma: implications for treatment. 2012

Leong, Stanley P L / Mihm, Martin C / Murphy, George F / Hoon, Dave S B / Kashani-Sabet, Mohammed / Agarwala, Sanjiv S / Zager, Jonathan S / Hauschild, Axel / Sondak, Vernon K / Guild, Valerie / Kirkwood, John M. ·Center for Melanoma Research and Treatment and Department of Surgery, California Pacific Medical Center, San Francisco, CA, USA. leongsx@cpmcri.org ·Clin Exp Metastasis · Pubmed #22892755.

ABSTRACT: The survival rates of melanoma, like any type of cancer, become worse with advancing stage. Spectrum theory is most consistent with the progression of melanoma from the primary site to the in-transit locations, regional or sentinel lymph nodes and beyond to the distant sites. Therefore, early diagnosis and surgical treatment before its spread is the most effective treatment. Recently, new approaches have revolutionized the diagnosis and treatment of melanoma. Genomic profiling and sequencing will form the basis for molecular taxonomy for more accurate subgrouping of melanoma patients in the future. New insights of molecular mechanisms of metastasis are summarized in this review article. Sentinel lymph node biopsy has become a standard of care for staging primary melanoma without the need for a more morbid complete regional lymph node dissection. With recent developments in molecular biology and genomics, novel molecular targeted therapy is being developed through clinical trials.

7 Review Cellular heterogeneity in vertical growth phase melanoma. 2010

Laga, Alvaro C / Murphy, George F. ·Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. alaga@rics.bwh.harvard.edu ·Arch Pathol Lab Med · Pubmed #21128771.

ABSTRACT: CONTEXT: Melanoma growing as a tumorigenic nodule is one of the most virulent neoplasms to which the flesh is heir. At a considerably small tumor size, it incurs significant risk for widespread metastatic dissemination. There are no effective means of surgical intervention, chemical therapy, or immunologic therapy for advanced and metastatic melanoma. OBJECTIVE: To review the literature and highlight recent cardinal advances in the understanding of melanoma vertical growth, with specific emphasis on how its recognition and characterization may be applied to diagnostic practice and development of novel investigative approaches. DATA SOURCES: Literature review, archival material, personal experience, and research collaborators. CONCLUSIONS: The study of tumorigenic melanoma, both in primary lesions and in metastases, is the key to the eventual eradication of this highly virulent neoplasm that may disseminate widely when only occupying the volume of a grain of rice. Morphology often provides the first insight into structure and function. A growing database using meticulous and inclusive criteria to define tumor stem cells in the context of clinically relevant models now indicates that the key to melanoma heterogeneity may reside in a small subpopulation with the ability to self-renew and form tumors despite most cells present being significantly less virulent. Hopefully, from these insights into melanoma tumor progression from radial growth phase to heterogeneous and tumorigenic vertical growth phase will come additional answers to how smart therapies may be developed that specifically target those vertical growth phase cells that most pertain to patient survival.

8 Clinical Trial Combined Anti-VEGF and Anti-CTLA-4 Therapy Elicits Humoral Immunity to Galectin-1 Which Is Associated with Favorable Clinical Outcomes. 2017

Wu, Xinqi / Li, Jingjing / Connolly, Erin M / Liao, Xiaoyun / Ouyang, Jing / Giobbie-Hurder, Anita / Lawrence, Donald / McDermott, David / Murphy, George / Zhou, Jun / Piesche, Matthias / Dranoff, Glenn / Rodig, Scott / Shipp, Margaret / Hodi, F Stephen. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Center for Immuno-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Department of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts. · Massachusetts General Hospital Cancer Center, Boston, Massachusetts. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile. · Novartis Institutes for BioMedical Research, Cambridge, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. stephen_hodi@dfci.harvard.edu. ·Cancer Immunol Res · Pubmed #28473314.

ABSTRACT: The combination of anti-VEGF blockade (bevacizumab) with immune checkpoint anti-CTLA-4 blockade (ipilimumab) in a phase I study showed tumor endothelial activation and immune cell infiltration that were associated with favorable clinical outcomes in patients with metastatic melanoma. To identify potential immune targets responsible for these observations, posttreatment plasma from long-term responding patients were used to screen human protein arrays. We reported that ipilimumab plus bevacizumab therapy elicited humoral immune responses to galectin-1 (Gal-1), which exhibits protumor, proangiogenesis, and immunosuppressive activities in 37.2% of treated patients. Gal-1 antibodies purified from posttreatment plasma suppressed the binding of Gal-1 to CD45, a T-cell surface receptor that transduces apoptotic signals upon binding to extracellular Gal-1. Antibody responses to Gal-1 were found more frequently in the group of patients with therapeutic responses and correlated with improved overall survival. In contrast, another subgroup of treated patients had increased circulating Gal-1 protein instead, and they had reduced overall survival. Our findings suggest that humoral immunity to Gal-1 may contribute to the efficacy of anti-VEGF and anti-CTLA-4 combination therapy. Gal-1 may offer an additional therapeutic target linking anti-angiogenesis and immune checkpoint blockade.

9 Clinical Trial Bevacizumab plus ipilimumab in patients with metastatic melanoma. 2014

Hodi, F Stephen / Lawrence, Donald / Lezcano, Cecilia / Wu, Xinqi / Zhou, Jun / Sasada, Tetsuro / Zeng, Wanyong / Giobbie-Hurder, Anita / Atkins, Michael B / Ibrahim, Nageatte / Friedlander, Philip / Flaherty, Keith T / Murphy, George F / Rodig, Scott / Velazquez, Elsa F / Mihm, Martin C / Russell, Sara / DiPiro, Pamela J / Yap, Jeffrey T / Ramaiya, Nikhil / Van den Abbeele, Annick D / Gargano, Maria / McDermott, David. ·Authors' Affiliations: Departments of Medical Oncology, Stephen_Hodi@dfci.harvard.edu. · Massachusetts General Hospital Cancer Center; Departments of. · University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; · Authors' Affiliations: Departments of Medical Oncology. · Biostatistics, and. · Lombardi Cancer Center Georgetown University, Washington, District of Columbia; and. · Mount Sinai Medical Center, New York, New York. · Pathology and. · Tufts University; Miraca Life Sciences, Newton, Massachusetts; · Surgery, Brigham and Women's Hospital; · Imaging, Dana-Farber Cancer Institute; · Beth Israel-Deaconess Medical Center, Boston; ·Cancer Immunol Res · Pubmed #24838938.

ABSTRACT: Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade.

10 Article Loss of GCNT2/I-branched glycans enhances melanoma growth and survival. 2018

Sweeney, Jenna Geddes / Liang, Jennifer / Antonopoulos, Aristotelis / Giovannone, Nicholas / Kang, Shuli / Mondala, Tony S / Head, Steven R / King, Sandra L / Tani, Yoshihiko / Brackett, Danielle / Dell, Anne / Murphy, George F / Haslam, Stuart M / Widlund, Hans R / Dimitroff, Charles J. ·Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. · Harvard Medical School, Boston, MA, 02115, USA. · Imperial College London, Division of Molecular Biosciences, Faculty of Natural Sciences, Biochemistry Building, London, SW7 2AZ, UK. · The Scripps Research Institute, La Jolla, CA, 92037, USA. · Japanese Red Cross Kinki Block Blood Center, 7-5-17 Saito Asagi, Ibaraki-shi, Osaka, 567-0085, Japan. · Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA. · Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. cdimitroff@bwh.harvard.edu. · Harvard Medical School, Boston, MA, 02115, USA. cdimitroff@bwh.harvard.edu. ·Nat Commun · Pubmed #30135430.

ABSTRACT: Cancer cells often display altered cell-surface glycans compared to their nontransformed counterparts. However, functional contributions of glycans to cancer initiation and progression remain poorly understood. Here, from expression-based analyses across cancer lineages, we found that melanomas exhibit significant transcriptional changes in glycosylation-related genes. This gene signature revealed that, compared to normal melanocytes, melanomas downregulate I-branching glycosyltransferase, GCNT2, leading to a loss of cell-surface I-branched glycans. We found that GCNT2 inversely correlated with clinical progression and that loss of GCNT2 increased melanoma xenograft growth, promoted colony formation, and enhanced cell survival. Conversely, overexpression of GCNT2 decreased melanoma xenograft growth, inhibited colony formation, and increased cell death. More focused analyses revealed reduced signaling responses of two representative glycoprotein families modified by GCNT2, insulin-like growth factor receptor and integrins. Overall, these studies reveal how subtle changes in glycan structure can regulate several malignancy-associated pathways and alter melanoma signaling, growth, and survival.

11 Article Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade. 2018

Shukla, Sachet A / Bachireddy, Pavan / Schilling, Bastian / Galonska, Christina / Zhan, Qian / Bango, Clyde / Langer, Rupert / Lee, Patrick C / Gusenleitner, Daniel / Keskin, Derin B / Babadi, Mehrtash / Mohammad, Arman / Gnirke, Andreas / Clement, Kendell / Cartun, Zachary J / Van Allen, Eliezer M / Miao, Diana / Huang, Ying / Snyder, Alexandra / Merghoub, Taha / Wolchok, Jedd D / Garraway, Levi A / Meissner, Alexander / Weber, Jeffrey S / Hacohen, Nir / Neuberg, Donna / Potts, Patrick R / Murphy, George F / Lian, Christine G / Schadendorf, Dirk / Hodi, F Stephen / Wu, Catherine J. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA. · Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), 69121 Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany. · Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. · Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. · Department of Pathology, University of Bern, 3012 Bern, Switzerland. · Broad Institute, Cambridge, MA 02142, USA. · Broad Institute, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. · Weill Cornell Medical College, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA. · Broad Institute, Cambridge, MA 02142, USA; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. · New York University Langone Medical Center, New York, NY 10016, USA. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. · Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA. · Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), 69121 Heidelberg, Germany. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA. Electronic address: cwu@partners.org. ·Cell · Pubmed #29656892.

ABSTRACT: CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.

12 Article 5-Hydroxymethylcytosine is a nuclear biomarker to assess biological potential in histologically ambiguous heavily pigmented melanocytic neoplasms. 2017

Lee, Jonathan J / Vilain, Ricardo E / Granter, Scott R / Hu, Nina R / Bresler, Scott C / Xu, Shuyun / Frank, Alexander H / Mihm, Martin C / Saw, Robyn P M / Fletcher, Christopher D / Scolyer, Richard A / Murphy, George F / Lian, Christine G. ·Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Melanoma Institute Australia, North Sydney, Australia. · Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. · Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Discipline of Surgery, Royal Prince Alfred Hospital, Sydney, NSW, Australia. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. ·J Cutan Pathol · Pubmed #28032662.

ABSTRACT: BACKGROUND: 5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker detectable through immunohistochemistry (IHC) that has been shown to distinguish benign nevi from melanoma with high sensitivity and specificity. The purpose of the study was to explore its diagnostic utility in a subset of histologically challenging, heavily pigmented cutaneous melanocytic neoplasms. METHODS: 5-hmC IHC was performed on 54 heavily pigmented melanocytic tumors. Semi-quantitative analysis of immunoreactivity was correlated with clinical, pathologic and follow-up data. RESULTS: Benign melanocytic neoplasms (4 of 4 blue nevi with epithelioid change; 12 of 12 combined nevi; 5 of 5 deep penetrating nevi, DPN) exhibited strong 5-hmC nuclear reactivity. Eight heavily pigmented blue nevus-like melanomas and 7 of 8 pigmented epithelioid melanocytomas (PEM) showed significant 5-hmC loss. Five of 7 atypical DPN cases and 8 of 10 melanocytic tumors of uncertain malignant potential (MELTUMP) showed low to intermediate 5-hmC immunoreactivity. These differences were statistically significant (P-value <.0001). CONCLUSIONS: Loss of 5-hmC may be helpful in differentiating benign, diagnostically challenging, heavily pigmented melanocytic tumors from those with malignant potential. The intermediate to low 5-hmC immunoreactivity in atypical DPNs, PEMs and so-called MELTUMP categories further underscores the need to consider these neoplasms as having some potential for lethal biological behavior.

13 Article Gene expression profiling of anti-CTLA4-treated metastatic melanoma in patients with treatment-induced autoimmunity. 2017

Bresler, Scott C / Min, Le / Rodig, Scott J / Walls, Andrew C / Xu, Shuyun / Geng, Songmei / Hodi, F Stephen / Murphy, George F / Lian, Christine G. ·Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. · Harvard Medical School, Boston, MA, USA. · Endocrinology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. · Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA. · Dana Farber Cancer Institute, Boston, MA, USA. ·Lab Invest · Pubmed #27918555.

ABSTRACT: Ipilimumab (IPI) is a monoclonal antibody that targets the inhibitory CTLA4 receptor of T cells, enhancing T-cell-driven antitumor responses. IPI therapy in metastatic melanoma results in significant improvement in disease-free and overall survival, although after initial responses disease progression generally ensues. Identification of specific responses in tissue where melanoma tumor cells are subjected to IPI-driven immune attack may reveal mechanisms of treatment efficacy or resistance, permitting refinement of targeted therapeutic approaches. We used NanoString digital barcoding chemistry to identify changes in the transcriptome of metastatic melanoma cells before and after IPI treatment using two comprehensive panels containing a total of 1330 unique genes. Only patients who developed autoimmune disorders following treatment, signifying a robust immune response, were included. Despite evidence of an enhanced immune response, most patients eventually exhibited disease progression. Overall, data from five pre-IPI tumors and four post-IPI tumor samples (from three patients) permitted identification of several candidate genes that showed increased expression based on normalized counts after therapy. These included TTK (~3.1-fold, P=1.18e-4), which encodes a dual-specificity protein tyrosine kinase, a known cell cycle regulator, and BIRC5 (~3.0-fold, P=9.36e-4), which encodes the antiapoptotic protein survivin. Both TTK (MPS1) and survivin are targetable proteins against which a number of pharmacologic agents have been developed. CDK1, which encodes a protein tyrosine kinase known to phosphorylate survivin, was also upregulated (~3.2-fold, P=2.80-3). Tumor cell expression of TTK and survivin proteins was confirmed using immunohistochemistry in an expanded patient cohort. Differences in gene expression for several commonly encountered immune antigens, such as CD3, CD4, CD8, and CTLA4, were not statistically significant, likely reflecting the long length of time (average 323 days) between the last IPI dose and post-treatment biopsies. Although our sample size is limited, these results for the first time identify targetable genes that are significantly altered by interaction between a highly activated, IPI-treated immune system and melanoma cells.

14 Article Targeting melanoma with front-line therapy does not abrogate Nodal-expressing tumor cells. 2017

Hendrix, Mary Jc / Kandela, Irawati / Mazar, Andrew P / Seftor, Elisabeth A / Seftor, Richard Eb / Margaryan, Naira V / Strizzi, Luigi / Murphy, George F / Long, Georgina V / Scolyer, Richard A. ·Department of Biology, Shepherd University, Shepherdstown, WV, USA. · Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. · Robert C. Byrd Health Sciences Center, West Virginia University Cancer Institute, West Virginia University, Morgantown, WV, USA. · Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA. · Department of Pathology, Midwestern University, Downers Grove, IL, USA. · Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. · Melanoma Institute Australia and Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. · Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. ·Lab Invest · Pubmed #27775691.

ABSTRACT: Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. It is the leading cause of skin cancer deaths with a median overall survival for advanced-stage metastatic disease of <6 months. Despite advances in the field with conventional and targeted therapies, the heterogeneity of melanoma poses the greatest ongoing challenge, ultimately leading to relapse and progression to a more drug-resistant tumor in most patients. Particularly noteworthy are recent findings, indicating that these therapies exert selective pressure on tumors resulting in the activation of pathways associated with cancer stem cells that are unresponsive to current therapy. Our previous studies have shown how Nodal, an embryonic morphogen of the transforming growth factor-beta superfamily, is one of these critical factors that is reactivated in aggressive melanoma and resistant to conventional chemotherapy, such as dacarbazine. In the current study, we sought to determine whether BRAF inhibitor (BRAFi) therapy targeted Nodal-expressing tumor cells in uniquely matched unresectable stage III and IV melanoma patient samples before and after therapy that preceded their eventual death due to disease. The results demonstrate that BRAFi treatment failed to affect Nodal levels in melanoma tissues. Accompanying experiments in soft agar and in nude mice showed the advantage of using combinatorial treatment with BRAFi plus anti-Nodal monoclonal antibody to suppress tumor growth and metastasis. These data provide a promising new approach using front-line therapy combined with targeting a cancer stem cell-associated molecule-producing a more efficacious response than monotherapy.

15 Article Mitochondrial DNA deletion percentage in sun exposed and non sun exposed skin. 2016

Powers, Julia M / Murphy, Gillian / Ralph, Nikki / O'Gorman, Susan M / Murphy, James E J. ·Mitochondrial Biology & Radiation Research Centre, Dept Life Sciences, IT Sligo, Sligo, Ireland. Electronic address: Julia.Powers@mail.itsligo.ie. · Department of Dermatology, Beaumont Hospital, Dublin, Ireland. · Mitochondrial Biology & Radiation Research Centre, Dept Life Sciences, IT Sligo, Sligo, Ireland. ·J Photochem Photobiol B · Pubmed #27829204.

ABSTRACT: The percentages of mitochondrial genomes carrying the mtDNA

16 Article Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. 2016

Tirosh, Itay / Izar, Benjamin / Prakadan, Sanjay M / Wadsworth, Marc H / Treacy, Daniel / Trombetta, John J / Rotem, Asaf / Rodman, Christopher / Lian, Christine / Murphy, George / Fallahi-Sichani, Mohammad / Dutton-Regester, Ken / Lin, Jia-Ren / Cohen, Ofir / Shah, Parin / Lu, Diana / Genshaft, Alex S / Hughes, Travis K / Ziegler, Carly G K / Kazer, Samuel W / Gaillard, Aleth / Kolb, Kellie E / Villani, Alexandra-Chloé / Johannessen, Cory M / Andreev, Aleksandr Y / Van Allen, Eliezer M / Bertagnolli, Monica / Sorger, Peter K / Sullivan, Ryan J / Flaherty, Keith T / Frederick, Dennie T / Jané-Valbuena, Judit / Yoon, Charles H / Rozenblatt-Rosen, Orit / Shalek, Alex K / Regev, Aviv / Garraway, Levi A. ·Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. · Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA. bizar@partners.org aregev@broadinstitute.org levi_garraway@dfci.harvard.edu. · Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Institute for Medical Engineering and Science, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Department of Chemistry, MIT, Cambridge, MA 02142, USA. Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Cambridge, MA 02139, USA. · Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Program in Therapeutic Sciences, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. · Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · HMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. · Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Institute for Medical Engineering and Science, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Cambridge, MA 02139, USA. Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA. · Department of Surgical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Department of Surgical Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Program in Therapeutic Sciences, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. HMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Ludwig Center at Harvard, Boston, MA 02215, USA. · Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. · Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Institute for Medical Engineering and Science, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Department of Chemistry, MIT, Cambridge, MA 02142, USA. Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Cambridge, MA 02139, USA. Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA. Department of Immunology, Massachusetts General Hospital, Boston, MA 02114, USA. · Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Department of Biology and Koch Institute, MIT, Boston, MA 02142, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. bizar@partners.org aregev@broadinstitute.org levi_garraway@dfci.harvard.edu. · Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. bizar@partners.org aregev@broadinstitute.org levi_garraway@dfci.harvard.edu. ·Science · Pubmed #27124452.

ABSTRACT: To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies.

17 Article TET2 Negatively Regulates Nestin Expression in Human Melanoma. 2016

Gomes, Camilla B F / Zechin, Karina G / Xu, Shuyun / Stelini, Rafael F / Nishimoto, Ines N / Zhan, Qian / Xu, Ting / Qin, Gungwei / Treister, Nathaniel S / Murphy, George F / Lian, Christine G. ·Program in Oral Pathology, Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba, Brazil; Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Program in Oral Pathology, Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba, Brazil. · Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Pathology, Medical Sciences School, University of Campinas, Piracicaba, Brazil. · Department of Head and Surgery and Otorhinolaryngology, A.C. Camargo Cancer Center, São Paulo, Brazil. · Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Harvard School of Dental Medicine, Boston, Massachusetts. · Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: gmurphy@rics.bwh.harvard.edu. · Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: cglian@bwh.harvard.edu. ·Am J Pathol · Pubmed #27102770.

ABSTRACT: Although melanoma is an aggressive cancer, the understanding of the virulence-conferring pathways involved remains incomplete. We have demonstrated that loss of ten-eleven translocation methylcytosine dioxygenase (TET2)-mediated 5-hydroxymethylcytosine (5-hmC) is an epigenetic driver of melanoma growth and a biomarker of clinical virulence. We also have determined that the intermediate filament protein nestin correlates with tumorigenic and invasive melanoma growth. Here we examine the relationships between these two biomarkers. Immunohistochemistry staining of nestin and 5-hmC in 53 clinically annotated primary and metastatic patient melanomas revealed a significant negative correlation. Restoration of 5-hmC, as assessed in a human melanoma cell line by introducing full-length TET2 and TET2-mutated constructs, decreased nestin gene and protein expression in vitro. Genome-wide mapping using hydroxymethylated DNA immunoprecipitation sequencing disclosed significantly less 5-hmC binding in the 3' untranslated region of the nestin gene in melanoma compared to nevi, and 5-hmC binding in this region was significantly increased after TET2 overexpression in human melanoma cells in vitro. Our findings provide evidence suggesting that nestin regulation is negatively controlled epigenetically by TET2 via 5-hmC binding at the 3' untranslated region of the nestin gene, providing one potential pathway for understanding melanoma growth characteristics. Studies are now indicated to further define the interplay between 5-hmC, nestin expression, and melanoma virulence.

18 Article Decreased tumor-infiltrating lymphocytes in nodular melanomas compared with matched superficial spreading melanomas. 2016

Lin, Richard L / Wang, Thomas J / Joyce, Cara J / Mihm, Martin C / Murphy, George F / Lian, Christine G / Lin, Jennifer Y. ·aHarvard Medical School bMihm Cutaneous Pathology Consultative Service cProgram in Dermatopathology, Department of Pathology dDepartment of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts eDepartment of Biostatistics, Tulane University, New Orleans, Louisiana, USA. ·Melanoma Res · Pubmed #26974966.

ABSTRACT: Melanoma causes over 9000 deaths annually in the USA. Among its subtypes, nodular melanoma leads to a disproportionate number of fatalities compared with superficial spreading melanoma, the most common subtype. Recent breakthroughs in melanoma research have indicated a strong connection between melanoma virulence and the immune system. We hypothesize that the aggression of nodular melanoma may, in part, be because of decreased recognition by the immune system, as represented by a decreased presence of tumor-infiltrating lymphocytes (TILs), compared with its superficial spreading counterpart. Indeed, TILs on a primary melanoma have been used as a marker for immune response and have prognostic value for survival and sentinel lymph node status. After matching melanoma cases by age, sex, and Breslow thickness, we found significantly fewer TILs in nodular melanomas than in superficial spreading melanomas. This association was prominent in thin (≤2 mm) melanomas and was no longer significant in thick (>2 mm) melanomas. In addition, this difference in TILs was only present in men and not in women. Our finding suggests that nodular melanomas are more frequently associated with absent TILs, providing an avenue for further investigation into differences in immunogenicity of the primary melanoma and whether they underlie the unique virulence of nodular melanoma.

19 Article Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis. 2015

Inada, Masaki / Takita, Morichika / Yokoyama, Satoshi / Watanabe, Kenta / Tominari, Tsukasa / Matsumoto, Chiho / Hirata, Michiko / Maru, Yoshiro / Maruyama, Takayuki / Sugimoto, Yukihiko / Narumiya, Shuh / Uematsu, Satoshi / Akira, Shizuo / Murphy, Gillian / Nagase, Hideaki / Miyaura, Chisato. ·From the Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, the Global Innovation Research Organization, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan. · From the Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, the Department of Pharmacology, Tokyo Women's Medical University, Tokyo 162-8666, Japan. · From the Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan. · the Department of Pharmacology, Tokyo Women's Medical University, Tokyo 162-8666, Japan. · the Minase Research Institutes, Ono Pharmaceutical Co. Ltd, Osaka 618-8585, Japan. · the Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Science, Kumamoto University, Kumamoto 862-0973, Japan. · the Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. · the Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan, the Department of Mucosal Immunology, School of Medicine, Chiba University, Chiba 260-8670, Japan, the Division of Innate Immune, Regulation, International Research, and Development, Center for Mucosal Vaccines, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. · the Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan. · the Global Innovation Research Organization, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, the Department of Oncology, University of Cambridge, Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom, and. · the Global Innovation Research Organization, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, the Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom. · From the Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, the Global Innovation Research Organization, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan, miyaura@cc.tuat.ac.jp. ·J Biol Chem · Pubmed #26475855.

ABSTRACT: The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1(-/-)) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4(-/-) mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors.

20 Article Loss of the epigenetic mark, 5-Hydroxymethylcytosine, correlates with small cell/nevoid subpopulations and assists in microstaging of human melanoma. 2015

Lee, Jonathan J / Cook, Martin / Mihm, Martin C / Xu, Shuyun / Zhan, Qian / Wang, Thomas J / Murphy, George F / Lian, Christine G. ·Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Department of Histopathology, Royal Surrey County Hospital, Guildford, United Kingdom. · Cancer Research UK, Manchester Institute, Manchester, United Kingdom. · Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ·Oncotarget · Pubmed #26462027.

ABSTRACT: Melanomas in the vertical growth phase (VGP) not infrequently demonstrate cellular heterogeneity. One commonly encountered subpopulation displays small cell/nevoid morphology. Although its significance remains unknown, such subpopulations may pose diagnostic issues when faced with differentiating such changes from associated nevus or mistaking such regions for nevic maturation (pseudomaturation). That 'loss' of the epigenetic biomarker, 5-hydroxymethylcytosine (5-hmC), is a hallmark for melanoma and correlates with virulence prompted us to explore the diagnostic utility and biological implications of 5-hmC immunohistochemistry (IHC) in melanomas with small cell/nevoid subpopulations. Fifty-two cases were included in this study, including melanomas with small cell/nevoid subpopulations (MSCN) or melanomas with pre-existing nevus (MPEN). Semiquantitative and computer-validated immunohistochemical analyses revealed invariable, uniform loss of 5-hmC in the conventional melanoma component. By contrast, the nevic components in MPEN cases demonstrated strong nuclear immunopositivity. In MSCN cases, there was partial to complete loss of 5-hmC restricted to these nevoid areas. Based on recent data supporting tight correlation between 5-hmC loss and malignancy, our findings indicate a potential 'intermediate' biological nature for small cell/nevoid subpopulations. Because 5-hmC assisted in differentiating such regions from associated nevus, the use of 5-hmC as an adjunct to microstaging in difficult cases showing VGP heterogeneity should be further explored.

21 Article Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. 2015

Kleffel, Sonja / Posch, Christian / Barthel, Steven R / Mueller, Hansgeorg / Schlapbach, Christoph / Guenova, Emmanuella / Elco, Christopher P / Lee, Nayoung / Juneja, Vikram R / Zhan, Qian / Lian, Christine G / Thomi, Rahel / Hoetzenecker, Wolfram / Cozzio, Antonio / Dummer, Reinhard / Mihm, Martin C / Flaherty, Keith T / Frank, Markus H / Murphy, George F / Sharpe, Arlene H / Kupper, Thomas S / Schatton, Tobias. ·Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Dermatology, The Rudolfstiftung Hospital, 1030 Vienna, Austria. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Dermatology, Innsbruck Medical University, 6020 Innsbruck, Austria. · Department of Dermatology, University of Bern, 3010 Bern, Switzerland. · Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA; School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. Electronic address: tschatton@bwh.harvard.edu. ·Cell · Pubmed #26359984.

ABSTRACT: Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy.

22 Article Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas. 2015

Lee, Jonathan J / Sholl, Lynette M / Lindeman, Neal I / Granter, Scott R / Laga, Alvaro C / Shivdasani, Priyanka / Chin, Gary / Luke, Jason J / Ott, Patrick A / Hodi, F Stephen / Mihm, Martin C / Lin, Jennifer Y / Werchniak, Andrew E / Haynes, Harley A / Bailey, Nancy / Liu, Robert / Murphy, George F / Lian, Christine G. ·Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, EBRC Suite 401, Boston, MA 02115 USA. · Melanoma Center, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA 02215-5450 USA. ·Clin Epigenetics · Pubmed #26221190.

ABSTRACT: BACKGROUND: Recent developments in genomic sequencing have advanced our understanding of the mutations underlying human malignancy. Melanoma is a prototype of an aggressive, genetically heterogeneous cancer notorious for its biologic plasticity and predilection towards developing resistance to targeted therapies. Evidence is rapidly accumulating that dysregulated epigenetic mechanisms (DNA methylation/demethylation, histone modification, non-coding RNAs) may play a central role in the pathogenesis of melanoma. Therefore, we sought to characterize the frequency and nature of mutations in epigenetic regulators in clinical, treatment-naïve, patient melanoma specimens obtained from one academic institution. RESULTS: Targeted next-generation sequencing for 275 known and investigative cancer genes (of which 41 genes, or 14.9 %, encoded an epigenetic regulator) of 38 treatment-naïve patient melanoma samples revealed that 22.3 % (165 of 740) of all non-silent mutations affected an epigenetic regulator. The most frequently mutated genes were BRAF, MECOM, NRAS, TP53, MLL2, and CDKN2A. Of the 40 most commonly mutated genes, 12 (30.0 %) encoded epigenetic regulators, including genes encoding enzymes involved in histone modification (MECOM, MLL2, SETD2), chromatin remodeling (ARID1B, ARID2), and DNA methylation and demethylation (TET2, IDH1). Among the 38 patient melanoma samples, 35 (92.1 %) harbored at least one mutation in an epigenetic regulator. The genes with the highest number of total UVB-signature mutations encoded epigenetic regulators, including MLL2 (100 %, 16 of 16) and MECOM (82.6 %, 19 of 23). Moreover, on average, epigenetic genes harbored a significantly greater number of UVB-signature mutations per gene than non-epigenetic genes (3.7 versus 2.4, respectively; p = 0.01). Bioinformatics analysis of The Cancer Genome Atlas (TCGA) melanoma mutation dataset also revealed a frequency of mutations in the 41 epigenetic genes comparable to that found within our cohort of patient melanoma samples. CONCLUSIONS: Our study identified a high prevalence of somatic mutations in genes encoding epigenetic regulators, including those involved in DNA demethylation, histone modification, chromatin remodeling, and microRNA processing. Moreover, UVB-signature mutations were found more commonly among epigenetic genes than in non-epigenetic genes. Taken together, these findings further implicate epigenetic mechanisms, particularly those involving the chromatin-remodeling enzyme MECOM/EVI1 and histone-modifying enzyme MLL2, in the pathobiology of melanoma.

23 Article Impact of the 2009 AJCC staging guidelines for melanoma on the number of mitotic figures reported by dermatopathologists at one institution. 2015

Larson, Allison R / Rothschild, Brian / Walls, Andrew C / Granter, Scott R / Qureshi, Abrar A / Murphy, George F / Laga, Alvaro C. ·Division of Dermatopathology, Department of Pathology, Brigham and Women's, Hospital, Harvard Medical School, Boston, MA, USA. · Department of Dermatology, Boston Medical Center, Boston, MA, USA. · Department of Dermatology, Colorado Permanente Medical Group, Denver, CO, USA. · Harvard Combined Dermatology Residency Program, Boston, MA, USA. · Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ·J Cutan Pathol · Pubmed #25929156.

ABSTRACT: BACKGROUND: In 2009 the revised seventh staging system for melanoma recommended the use of mitotic count to separate stage T1a from T1b. However, careful scrutiny of cases may lead to an inadvertent selection effect, with consequent increased reporting of mitotic counts. METHODS: We investigated whether there is a significant increase in mitotic counts reported since 2009 for melanomas with a Breslow thickness of 1.0 mm or less. We conducted a retrospective, case-controlled study examining invasive melanoma cases at a large academic center. Mitotic counts were compared between pathology reports before 2009 (n = 61) and after 2009 (n = 125), with a subset of slides re-examined in a blinded fashion. RESULTS: Before the 2009 staging guidelines, 51% of cases had one or more mitosis reported compared to 38% after 2009 (p = 0.113). Blinded re-counting did not yield a significant difference when compared with the original pathology reports in either group. CONCLUSIONS: There was not a significant difference in the number of mitoses reported after the implementation of the new guidelines.

24 Article Targeting nodal in conjunction with dacarbazine induces synergistic anticancer effects in metastatic melanoma. 2015

Hardy, Katharine M / Strizzi, Luigi / Margaryan, Naira V / Gupta, Kanika / Murphy, George F / Scolyer, Richard A / Hendrix, Mary J C. ·Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. · Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Howard Hughes Medical Institute NU Bioscientist Program, Weinberg College of Arts and Sciences, Northwestern University, Evanston, Illinois. · Department of Pathology, Harvard Medical School, Brigham & Women's Hospital, Boston, Massachusetts. · Melanoma Institute Australia; Sydney Medical School, The University of Sydney; and Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. · Program in Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute at Ann and Robert H. Lurie Children's Hospital of Chicago, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. m-hendrix@northwestern.edu. ·Mol Cancer Res · Pubmed #25767211.

ABSTRACT: IMPLICATIONS: Targeting Nodal in combination with DTIC therapy holds promise for the treatment of metastatic melanoma.

25 Article Melanoma Cell Galectin-1 Ligands Functionally Correlate with Malignant Potential. 2015

Yazawa, Erika M / Geddes-Sweeney, Jenna E / Cedeno-Laurent, Filiberto / Walley, Kempland C / Barthel, Steven R / Opperman, Matthew J / Liang, Jennifer / Lin, Jennifer Y / Schatton, Tobias / Laga, Alvaro C / Mihm, Martin C / Qureshi, Abrar A / Widlund, Hans R / Murphy, George F / Dimitroff, Charles J. ·Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA. · Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Dermatology, The Warren Albert Medical School, Brown University, Providence, Rhode Island, USA. · Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA. Electronic address: cdimitroff@rics.bwh.harvard.edu. ·J Invest Dermatol · Pubmed #25756799.

ABSTRACT: Galectin-1 (Gal-1)-binding to Gal-1 ligands on immune and endothelial cells can influence melanoma development through dampening antitumor immune responses and promoting angiogenesis. However, whether Gal-1 ligands are functionally expressed on melanoma cells to help control intrinsic malignant features remains poorly understood. Here, we analyzed expression, identity, and function of Gal-1 ligands in melanoma progression. Immunofluorescent analysis of benign and malignant human melanocytic neoplasms revealed that Gal-1 ligands were abundant in severely dysplastic nevi, as well as in primary and metastatic melanomas. Biochemical assessments indicated that melanoma cell adhesion molecule (MCAM) was a major Gal-1 ligand on melanoma cells that was largely dependent on its N-glycans. Other melanoma cell Gal-1 ligand activity conferred by O-glycans was negatively regulated by α2,6 sialyltransferase ST6GalNAc2. In Gal-1-deficient mice, MCAM-silenced (MCAM(KD)) or ST6GalNAc2-overexpressing (ST6(O/E)) melanoma cells exhibited slower growth rates, underscoring a key role for melanoma cell Gal-1 ligands and host Gal-1 in melanoma growth. Further analysis of MCAM(KD) or ST6(O/E) melanoma cells in cell migration assays indicated that Gal-1 ligand-dependent melanoma cell migration was severely inhibited. These findings provide a refined perspective on Gal-1/melanoma cell Gal-1 ligand interactions as contributors to melanoma malignancy.

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