Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Melanoma: HELP
Articles by Dave S. B. Hoon
Based on 70 articles published since 2008
||||

Between 2008 and 2019, D. Hoon wrote the following 70 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Liquid Biopsies for Assessing Metastatic Melanoma Progression. 2016

Huynh, Kelly / Hoon, Dave S B. ·Department of Surgical Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA 90404. · Department of Molecular Oncology John Wayne Cancer Institute at Providence Saint John's Health Center Santa Monica, California. ·Crit Rev Oncog · Pubmed #27481010.

ABSTRACT: The field of genomic biomarkers in melanoma has evolved dramatically in the past few decades. Whereas much of the prior focus was on molecular assessment of tumor tissue, circulating tumor cells (CTCs), and cell-free circulating tumor DNA (ctDNA) as sources of a "liquid biopsy" in cancer patients provide promising potential as a method to assess tumor progression, identify targets for therapy, and evaluate clinical response to treatment. Blood biomarker assays have the advantage of being noninvasive, allow for dynamic evaluation of disease over a serial time frame, and help to address the issue of tissue sampling bias and tumor heterogeneity. However, there remains an assortment of technologies and techniques to isolate and detect CTCs and ctDNA and a standardized method has yet to be established. Despite these challenges, multiple studies have already demonstrated the clinical prognostic utility of blood-based genomic biomarker assays. With the advent of next-generation sequencing and genome-wide ctDNA analysis, this will undoubtedly lead to an improved understanding of tumor progression, help to identify new targets for treatment, and improve monitoring of treatment response and development of resistance.

2 Review Liquid biopsy utility for the surveillance of cutaneous malignant melanoma patients. 2016

Huang, Sharon K / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA 90404, United States. · Department of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA 90404, United States. Electronic address: hoond@jwci.org. ·Mol Oncol · Pubmed #26778792.

ABSTRACT: Cutaneous melanoma is one of the highest incident-rate cancers with increasing prevalence in Western societies. Despite the advent of new approved therapeutics, the 5-year overall survival rate of stage IV melanoma patients remains below 15%. Current treatments for late stage disease have shown higher efficacy when treated at a lower disease burden. Thus, blood-based biomarkers capable of detecting melanoma prior to clinically evident distant metastasis, will improve the treatment and outcomes for melanoma patients. To that end, effective treatment of melanoma necessitates identification of patients at risk for developing distant metastases. Furthermore, employing blood biomarkers that monitor cancer progression over the course of treatment is a promising solution to post-treatment drug resistance often developed in melanoma patients. Non-invasive blood biomarker assays allow for regular dynamic monitoring of disease. "Liquid Biopsy" of blood, which exploits circulating tumor cells (CTCs), cell-free circulating tumor DNA (ctDNA) and cell-free circulating microRNA (cmiRNA), has been shown to detect prognostic factors for relapse in AJCC stage III and stage IV melanoma patients. Moreover, molecular characterization of CTC and analysis of various forms of ctDNA present promising potential in development of individualized therapy for melanoma patients. New approaches such as massive parallel sequencing (MPS) provide a comprehensive view of the disease progression, allowing for the selection of therapeutic options for individual patients. With advancements of improving molecular assays, liquid biopsy analysis as a powerful, routine clinical assay for melanoma patients, is highly promising prospective.

3 Review Epigenomic landscape of melanoma progression to brain metastasis: unexplored therapeutic alternatives. 2015

Marzese, Diego M / Witz, Isaac P / Kelly, Daniel F / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, 2200 Santa Monica Boulevard, Santa Monica, CA 90404, USA. · Department of Cell Research & Immunology, George S. Wise, Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. · Brain Tumor Center, Providence Saint John's Health Center, Santa Monica, CA 90404, USA. ·Epigenomics · Pubmed #26638944.

ABSTRACT: Melanoma brain metastasis is a complication with rising incidence. Despite the high rate of somatic mutations driving the initial stages of melanocyte transformation, the brain colonization requires a phenotypic reprogramming that is, in part, influenced by epigenomic modifications. This special report summarizes recent findings in the epigenomic landscape of melanoma progression to brain metastasis, with particular emphasis on the clinical utility of DNA methylation, chromatin modifications and ncRNA expression as theragnostic markers, as well as the significance of the metastatic microenvironment on melanoma brain metastasis epigenome.

4 Review Epigenetic biomarkers in skin cancer. 2014

Greenberg, Edward S / Chong, Kelly K / Huynh, Kelly T / Tanaka, Ryo / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA, USA. ·Cancer Lett · Pubmed #22289720.

ABSTRACT: Epigenetic aberrations have been associated with cutaneous melanoma tumorigenesis and progression including dysregulated DNA gene promoter region methylation, histone modification, and microRNA. Several of these major epigenetic aberrations have been developed into biomarkers. Epigenetic biomarkers can be detected in tissue and in blood as circulating DNA in melanoma patients. There is strong evidence that biomarkers in cutaneous melanoma will have an important role as companions to therapeutics and overall patient management. Important progress has been made in epigenetic melanoma biomarker development and verification of clinical utility, and this review discusses some of the key current developments and existing challenges.

5 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.

6 Review Epigenetics of regional lymph node metastasis in solid tumors. 2012

Huynh, Kelly T / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404, USA. ·Clin Exp Metastasis · Pubmed #22684433.

ABSTRACT: Regional nodal status remains one of the most important prognostic factors in several solid tumors including melanoma, breast cancer, and gastrointestinal malignancies. However, despite the accuracy of lymph node (LN) staging, patients who are LN negative are still at risk for development of recurrence and distant metastasis. As such, numerous molecular studies have focused on genetic and transcriptome changes in primary and metastatic tumors to discover molecular determinants that can predict aggressive metastatic disease and/or correlated to clinical outcomes. More recently, epigenetic aberrations have been investigated in solid cancers and are associated with tumorigenesis and disease progression. These epigenetic alterations have demonstrated potential utility as diagnostic and prognostic biomarkers and are being developed into novel targeted treatment strategies, as epigenetic changes can be reversed by appropriate drugs. If patients who are at increased risk of developing metastases or recurrence can be accurately identified, this will help stratify patients into more appropriate treatment and follow-up. This review discusses some of the recent studies on regional LN metastases in melanoma, breast cancer, and colorectal cancer, focusing on the potential clinicopathological utility of epigenetic aberrations in the management of cancer patients.

7 Review Prognostic molecular biomarkers for cutaneous malignant melanoma. 2011

Tanaka, Ryo / Koyanagi, Kazuo / Narita, Norihiko / Kuo, Christine / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California, USA. ·J Surg Oncol · Pubmed #21557225.

ABSTRACT: Molecular signatures of melanoma have propelled new approaches to early diagnosis, monitoring of treatment response, and targeted therapy. This review discusses messenger RNA (mRNA), genomic, and epigenomic melanoma biomarkers in blood and tissue specimens. The major focus is on tissue-based molecular assays to upstage sentinel lymph nodes (SLNs), and blood-based assays to detect melanoma progression by monitoring levels of circulating tumor cells (CTC) and circulating DNA.

8 Review Molecular mechanisms of metastasis. 2011

Hoon, Dave S B / Ferris, Robert / Tanaka, Ryo / Chong, Kelly K / Alix-Panabières, Catherine / Pantel, Klaus. ·Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California 90404, USA. hoon@jwci.org ·J Surg Oncol · Pubmed #21480243.

ABSTRACT: The mechanism of metastasis is a complex set of events that build upon each other to achieve successful growth in organ sites beyond the primary tumor. The cumulative events for metastasis of different cancers have both common and specific cancer specific events. This review discusses several key factors in different cancers that are responsible in metastasis, which includes epigenetic regulation of tumor suppressor genes, functional activity of tumor-related chemokine receptors, and circulating tumor cells.

9 Clinical Trial Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. 2017

Faries, Mark B / Thompson, John F / Cochran, Alistair J / Andtbacka, Robert H / Mozzillo, Nicola / Zager, Jonathan S / Jahkola, Tiina / Bowles, Tawnya L / Testori, Alessandro / Beitsch, Peter D / Hoekstra, Harald J / Moncrieff, Marc / Ingvar, Christian / Wouters, Michel W J M / Sabel, Michael S / Levine, Edward A / Agnese, Doreen / Henderson, Michael / Dummer, Reinhard / Rossi, Carlo R / Neves, Rogerio I / Trocha, Steven D / Wright, Frances / Byrd, David R / Matter, Maurice / Hsueh, Eddy / MacKenzie-Ross, Alastair / Johnson, Douglas B / Terheyden, Patrick / Berger, Adam C / Huston, Tara L / Wayne, Jeffrey D / Smithers, B Mark / Neuman, Heather B / Schneebaum, Schlomo / Gershenwald, Jeffrey E / Ariyan, Charlotte E / Desai, Darius C / Jacobs, Lisa / McMasters, Kelly M / Gesierich, Anja / Hersey, Peter / Bines, Steven D / Kane, John M / Barth, Richard J / McKinnon, Gregory / Farma, Jeffrey M / Schultz, Erwin / Vidal-Sicart, Sergi / Hoefer, Richard A / Lewis, James M / Scheri, Randall / Kelley, Mark C / Nieweg, Omgo E / Noyes, R Dirk / Hoon, Dave S B / Wang, He-Jing / Elashoff, David A / Elashoff, Robert M. ·From the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica (M.B.F., D.S.B.H.), and the Departments of Pathology (A.J.C.), Biomathematics (H.-J.W., D.A.E., R.M.E.), and Medicine (D.A.E.), University of California, Los Angeles - both in California · Melanoma Institute Australia and the University of Sydney, Sydney (J.F.T., O.E.N.), Peter MacCallum Cancer Centre, Melbourne, VIC (M.H.), Princess Alexandra Hospital, Brisbane, QLD (B.M.S.), and Newcastle Melanoma Unit, Waratah, NSW (P.H.) - all in Australia · Huntsman Cancer Institute, Salt Lake City (R.H.A., R.D.N.), and Intermountain Healthcare Cancer Services-Intermountain Medical Center, Murray (T.L.B.) - both in Utah · Istituto Nazionale dei Tumori Napoli, Naples (N.M.), Istituto Europeo di Oncologia, Milan (A.T.), and Istituto Oncologico Veneto-University of Padua, Padua (C.R.R.) - all in Italy · H. Lee Moffitt Cancer Center, Tampa, FL (J.S.Z.) · Helsinki University Hospital, Helsinki (T.J.) · Dallas Surgical Group, Dallas (P.D.B.) · Universitair Medisch Centrum Groningen, Groningen (H.J.H.), and Netherlands Cancer Institute, Amsterdam (M.W.J.M.W.) - both in the Netherlands · Norfolk and Norwich University Hospital, Norwich (M. Moncrieff), and Guy's and St. Thomas' NHS Foundation Trust, London (A.M.-R.) - both in the United Kingdom · Swedish Melanoma Study Group-University Hospital Lund, Lund, Sweden (C.I.) · University of Michigan, Ann Arbor (M.S.S.) · Wake Forest University, Winston-Salem (E.A.L.), and Duke University, Durham (R.S.) - both in North Carolina · Ohio State University, Columbus (D.A.) · University of Zurich, Zurich (R.D.), and Centre Hospitalier Universitaire Vaudois, Lausanne (M. Matter) - both in Switzerland · Penn State Hershey Cancer Institute, Hershey (R.I.N.), Thomas Jefferson University (A.C.B.) and Fox Chase Cancer Center (J.M.F.), Philadelphia, and St. Luke's University Health Network, Bethlehem (D.C.D.) - all in Pennsylvania · Greenville Health System Cancer Center, Greenville, SC (S.D.T.) · Sunnybrook Research Institute, Toronto (F.W.), and Tom Baker Cancer Centre, Calgary, AB (G.M.) - both in Canada · University of Washington, Seattle (D.R.B.) · Saint Louis University, St. Louis (E.H.) · Vanderbilt University (D.B.J., M.C.K.), Nashville, and University of Tennessee, Knoxville (J.M.L.) - both in Tennessee · University Hospital Schleswig-Holstein-Campus Lübeck, Lübeck (P.T.), University Hospital of Würzburg, Würzburg (A.G.), and City Hospital of Nürnberg, Nuremberg (E.S.) - all in Germany · SUNY at Stony Brook Hospital Medical Center, Stony Brook (T.L.H.), Memorial Sloan Kettering Cancer Center, New York (C.E.A.), and Roswell Park Cancer Institute, Buffalo (J.M.K.) - all in New York · Northwestern University Feinberg School of Medicine (J.D.W.) and Rush University Medical Center (S.D.B.), Chicago · University of Wisconsin, Madison (H.B.N.) · Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (S.S.) · M.D. Anderson Medical Center, Houston (J.E.G.) · Johns Hopkins University School of Medicine, Baltimore (L.J.) · University of Louisville, Louisville, KY (K.M.M.) · Dartmouth-Hitchcock Medical Center, Lebanon, NH (R.J.B.) · Hospital Clinic Barcelona, Barcelona (S.V.-S.) · and Sentara CarePlex Hospital, Hampton, VA (R.A.H.). ·N Engl J Med · Pubmed #28591523.

ABSTRACT: BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

10 Clinical Trial A direct plasma assay of circulating microRNA-210 of hypoxia can identify early systemic metastasis recurrence in melanoma patients. 2015

Ono, Shigeshi / Oyama, Takashi / Lam, Stella / Chong, Kelly / Foshag, Leland J / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA. · Division of Surgical Oncology, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA. ·Oncotarget · Pubmed #25749524.

ABSTRACT: Circulating cell-free(cf) microRNAs (miRNAs) have been reported to exist in plasma. MicroRNA-210(miR-210) is known to play important roles in the tumor hypoxic state. We hypothesized that the expression levels of cf-miR-210 in plasma would predict early clinical recurrence in melanoma patients. A direct miRNA assay on plasma (RT-qPCR-DP) was developed to improve cf-miRNA assay logistics, eliminate RNA extraction, and reduce specimen amount required. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) melanoma tissues (n = 108) and assessed by RT-qPCR. Plasma (10 μl; n = 264) was procured from AJCC Stage III/IV patients in phase III clinical trials. A RT-qPCR-DP was performed to detect cf-miR-210. MiR-210 was significantly higher in metastatic tumors compared to primary tumors. Cf-miR-210 was significantly higher in melanoma patients versus healthy donor controls. In serial bloods within individual patients, cf-miR-210 < 3 months prior to disease recurrence significantly increased compared to baseline levels (p = 0.012). ROC curve analysis demonstrated that patients with elevated cf-miR-210 were more likely to have disease recurrence. Moreover, cf-miR-210 increase significantly correlated with poorer prognosis (p < 0.001). Lactate dehydrogenase (LDH) level was also assessed within patients, and the AIC values for proportional hazards regression models of cf-miR-210(120.01) and LDH (122.91) demonstrated that cf-miR-210 is a better recurrence indicator. We concluded enhanced cf-miR-210 provides identification of early systemic melanoma recurrence.

11 Clinical Trial Association between circulating tumor cells and prognosis in patients with stage III melanoma with sentinel lymph node metastasis in a phase III international multicenter trial. 2012

Hoshimoto, Sojun / Shingai, Tatsushi / Morton, Donald L / Kuo, Christine / Faries, Mark B / Chong, Kelly / Elashoff, David / Wang, He-Jing / Elashoff, Robert M / Hoon, Dave S B. ·John Wayne Cancer Institute at Saint John's Health Center, 2200 Santa Monica Blvd, Santa Monica, CA 90404, USA. ·J Clin Oncol · Pubmed #23008288.

ABSTRACT: PURPOSE: The outcomes of patients with melanoma who have sentinel lymph node (SLN) metastases can be highly variable, which has precluded establishment of consensus regarding treatment of the group. The detection of high-risk patients from this clinical setting may be helpful for determination of both prognosis and management. We report the utility of multimarker reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) detection of circulating tumor cells (CTCs) in patients with melanoma diagnosed with SLN metastases in a phase III, international, multicenter clinical trial. PATIENTS AND METHODS: Blood specimens were collected from patients with melanoma (n = 331) who were clinically disease-free after complete lymphadenectomy (CLND) before entering onto a randomized adjuvant melanoma vaccine plus bacillus Calmette-Guérin (BCG) versus BCG placebo trial from 30 melanoma centers (United States and international). Blood was assessed using a verified multimarker RT-qPCR assay (MART-1, MAGE-A3, and GalNAc-T) of melanoma-associated proteins. Cox regression analyses were used to evaluate the prognostic significance of CTC status for disease recurrence and melanoma-specific survival (MSS). RESULTS: Individual CTC biomarker detection ranged from 13.4% to 17.5%. There was no association of CTC status (zero to one positive biomarkers v two or more positive biomarkers) with known clinical or pathologic prognostic variables. However, two or more positive biomarkers was significantly associated with worse distant metastasis disease-free survival (hazard ratio [HR] = 2.13, P = .009) and reduced recurrence-free survival (HR = 1.70, P = .046) and MSS (HR = 1.88, P = .043) in a multivariable analysis. CONCLUSION: CTC biomarker status is a prognostic factor for recurrence-free survival, distant metastasis disease-free survival, and MSS after CLND in patients with SLN metastasis. This multimarker RT-qPCR analysis may therefore be useful in discriminating patients who may benefit from aggressive adjuvant therapy or stratifying patients for adjuvant clinical trials.

12 Clinical Trial Assessment of prognostic circulating tumor cells in a phase III trial of adjuvant immunotherapy after complete resection of stage IV melanoma. 2012

Hoshimoto, Sojun / Faries, Mark B / Morton, Donald L / Shingai, Tatsushi / Kuo, Christine / Wang, He-Jing / Elashoff, Robert / Mozzillo, Nicola / Kelley, Mark C / Thompson, John F / Lee, Jeffrey E / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA. ·Ann Surg · Pubmed #22202581.

ABSTRACT: OBJECTIVE: To verify circulating tumor cell (CTC) prognostic utility in stage IV resected melanoma patients in a prospective international phase III clinical trial. BACKGROUND: Our studies of melanoma patients in phase II clinical trials demonstrated prognostic significance for CTCs in patients with AJCC stage IV melanoma. CTCs were assessed to determine prognostic utility in follow-up of disease-free stage IV patients pre- and during treatment. METHODS: After complete metastasectomy, patients were prospectively enrolled in a randomized trial of adjuvant therapy with a whole-cell melanoma vaccine, Canvaxin, plus Bacille Calmette-Guerin (BCG) versus placebo plus BCG. Blood specimens obtained pretreatment (n = 244) and during treatment (n = 214) were evaluated by quantitative real-time reverse-transcriptase polymerase chain reaction (qPCR) for expression of MART-1, MAGE-A3, and PAX3 mRNA biomarkers. Univariate and multivariate Cox analyses examined CTC biomarker expression with respect to clinicopathological variables. RESULTS: CTC biomarker(s) (≥ 1) was detected in 54% of patients pretreatment and in 86% of patients over the first 3 months. With a median follow-up of 21.9 months, 71% of patients recurred and 48% expired. CTC levels were not associated with known prognostic factors or treatment arm. In multivariate analysis, pretreatment CTC (> 0 vs. 0 biomarker) status was significantly associated with disease-free survival (DFS; HR 1.64, P = 0.002) and overall survival (OS; HR 1.53, P = 0.028). Serial CTC (>0 vs. 0 biomarker) status was also significantly associated with DFS (HR 1.91, P = 0.02) and OS (HR 2.57, P = 0.012). CONCLUSION: CTC assessment can provide prognostic discrimination before and during adjuvant treatment for resected stage IV melanoma patients.

13 Article The metastatic microenvironment: Melanoma-microglia cross-talk promotes the malignant phenotype of melanoma cells. 2019

Izraely, Sivan / Ben-Menachem, Shlomit / Sagi-Assif, Orit / Telerman, Alona / Zubrilov, Inna / Ashkenazi, Ofir / Meshel, Tsipi / Maman, Shelly / Orozco, Javier I J / Salomon, Matthew P / Marzese, Diego M / Pasmanik-Chor, Metsada / Pikarski, Eli / Ehrlich, Marcelo / Hoon, Dave S B / Witz, Isaac P. ·Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel. · Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA. · Bioinforamatics Unit, The George S. Wise Faculty of Life Science, Tel Aviv University, Tel-Aviv, Israel. · The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem, Israel. ·Int J Cancer · Pubmed #29992556.

ABSTRACT: Melanoma has the highest propensity to metastasize to the brain compared to other cancers, as brain metastases are found frequently high in patients who have prolonged survival with visceral metastasis. Once disseminated in the brain, melanoma cells communicate with brain resident cells that include astrocytes and microglia. Microglia cells are the resident macrophages of the brain and are the main immunological cells in the CNS involved in neuroinflammation. Data on the interactions between brain metastatic melanoma cells and microglia and on the role of microglia-mediated neuroinflammation in facilitating melanoma brain metastasis are lacking. To elucidate the role of microglia in melanoma brain metastasis progression, we examined the bidirectional interactions between microglia and melanoma cells in the tumor microenvironment. We identified the molecular and functional modifications occurring in brain-metastasizing melanoma cells and microglia cells after the treatment of each cell type with supernatants of the counter cell type. Both cells induced alteration in gene expression programs, cell signaling, and cytokine secretion in the counter cell type. Moreover, melanoma cells exerted significant morphological changes on microglia cells, enhanced proliferation, induced matrix metalloproteinase-2 (MMP-2) activation, and cell migration. Microglia cells induced phenotypic changes in melanoma cells increasing their malignant phenotype: increased melanoma proliferation, MMP-2 activity, cell migration, brain endothelial penetration, and tumor cells ability to grow as spheroids in 3D cultures. Our work provides a novel insight into the bidirectional interactions between melanoma and micoglia cells, suggesting the contribution of microglia to melanoma brain metastasis formation.

14 Article Epigenetic profiling for the molecular classification of metastatic brain tumors. 2018

Orozco, Javier I J / Knijnenburg, Theo A / Manughian-Peter, Ayla O / Salomon, Matthew P / Barkhoudarian, Garni / Jalas, John R / Wilmott, James S / Hothi, Parvinder / Wang, Xiaowen / Takasumi, Yuki / Buckland, Michael E / Thompson, John F / Long, Georgina V / Cobbs, Charles S / Shmulevich, Ilya / Kelly, Daniel F / Scolyer, Richard A / Hoon, Dave S B / Marzese, Diego M. ·Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, 90404, USA. · Institute for Systems Biology, Seattle, WA, 98109, USA. · Pacific Neuroscience Institute, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, 90404, USA. · Department of Pathology, Providence Saint John's Health Center, Santa Monica, CA, 90404, USA. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, 2065, Australia. · Ben & Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, 98122, USA. · Department of Neuropathology, Royal Prince Alfred Hospital, the Brain and Mind Centre, The University of Sydney, Camperdown, NSW, 2050, Australia. · Sydney Medical School, The University of Sydney, Camperdown, NSW, 2006, Australia. · Royal North Shore Hospital, Sydney, NSW, 2065, Australia. · Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia. · Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, 90404, USA. · Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, 90404, USA. MarzeseD@jwci.org. ·Nat Commun · Pubmed #30401823.

ABSTRACT: Optimal treatment of brain metastases is often hindered by limitations in diagnostic capabilities. To meet this challenge, here we profile DNA methylomes of the three most frequent types of brain metastases: melanoma, breast, and lung cancers (n = 96). Using supervised machine learning and integration of DNA methylomes from normal, primary, and metastatic tumor specimens (n = 1860), we unravel epigenetic signatures specific to each type of metastatic brain tumor and constructed a three-step DNA methylation-based classifier (BrainMETH) that categorizes brain metastases according to the tissue of origin and therapeutically relevant subtypes. BrainMETH predictions are supported by routine histopathologic evaluation. We further characterize and validate the most predictive genomic regions in a large cohort of brain tumors (n = 165) using quantitative-methylation-specific PCR. Our study highlights the importance of brain tumor-defining epigenetic alterations, which can be utilized to further develop DNA methylation profiling as a critical tool in the histomolecular stratification of patients with brain metastases.

15 Article Predominance of triple wild-type and IGF2R mutations in mucosal melanomas. 2018

Iida, Yuuki / Salomon, Matthew P / Hata, Keisuke / Tran, Kevin / Ohe, Shuichi / Griffiths, Chester F / Hsu, Sandy C / Nelson, Nellie / Hoon, Dave S B. ·Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, 90404, USA. · Brain Tumor Center, Providence Saint John's Health Center, Santa Monica, CA, USA. · John Wayne Cancer Institute Genome Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. · Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, 90404, USA. hoond@jwci.org. ·BMC Cancer · Pubmed #30373548.

ABSTRACT: BACKGROUND: Primary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa. MM has not been well profiled for mutations and its etiology is not well understood, rendering current treatment strategies unsuccessful. Hence, we investigated mutational landscape for MM to understand its etiology and to clarify mutations that are potentially relevant for MM treatment. METHODS: Forty one MM and 48 cutaneous melanoma (CM) tissues were profiled for mutations using targeted deep next-generation sequencing (NGS) for 89 cancer-related genes. A total of 997 mutations within exons were analyzed for their mutational spectrum and prevalence of mutation, and 685 non-synonymous variants were investigated to identify mutations in individual genes and pathways. PD-L1 expression from 21 MM and 18 CM were assessed by immunohistochemistry. RESULTS: Mutational spectrum analysis revealed a lower frequency of UV-induced DNA damage in MM than in CM (p = 0.001), while tobacco exposure was indicated as a potential etiologic factor for MM. In accordance with low UV damage signatures, MM demonstrated an overall lower number of mutations compared to CM (6.5 mutations/Mb vs 14.8 mutations/Mb, p = 0.001), and less PD-L1 expression (p = 0.003). Compared to CM, which showed frequent mutations in known driver genes (BRAF 50.0%, NRAS 29.2%), MM displayed lower mutation frequencies (BRAF; 12.2%, p < 0.001, NRAS; 17.1%), and was significantly more enriched for triple wild-type (no mutations in BRAF, RAS, or NF1, 70.7% vs 25.0%, p < 0.001), IGF2R mutation (31.7% vs 6.3%, p = 0.002), and KIT mutation (9.8% vs 0%, p = 0.042). Of clinical relevance, presence of DCC mutations was significantly associated with poorer overall survival in MM (log-rank test, p = 0.02). Furthermore, mutational spectrum analysis distinguished primary anorectal MM from CM metastasized to the bowel (spectrum analysis p < 0.001, number of mutations p = 0.002). CONCLUSIONS: These findings demonstrated a potential etiologic factor and driver mutation for MM and strongly suggested that MM initiation or progression involves distinct molecular-mechanisms from CM. This study also identified mutational signatures that are clinically relevant for MM treatment.

16 Article A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma. 2017

Krepler, Clemens / Sproesser, Katrin / Brafford, Patricia / Beqiri, Marilda / Garman, Bradley / Xiao, Min / Shannan, Batool / Watters, Andrea / Perego, Michela / Zhang, Gao / Vultur, Adina / Yin, Xiangfan / Liu, Qin / Anastopoulos, Ioannis N / Wubbenhorst, Bradley / Wilson, Melissa A / Xu, Wei / Karakousis, Giorgos / Feldman, Michael / Xu, Xiaowei / Amaravadi, Ravi / Gangadhar, Tara C / Elder, David E / Haydu, Lauren E / Wargo, Jennifer A / Davies, Michael A / Lu, Yiling / Mills, Gordon B / Frederick, Dennie T / Barzily-Rokni, Michal / Flaherty, Keith T / Hoon, Dave S / Guarino, Michael / Bennett, Joseph J / Ryan, Randall W / Petrelli, Nicholas J / Shields, Carol L / Terai, Mizue / Sato, Takami / Aplin, Andrew E / Roesch, Alexander / Darr, David / Angus, Steve / Kumar, Rakesh / Halilovic, Ensar / Caponigro, Giordano / Jeay, Sebastien / Wuerthner, Jens / Walter, Annette / Ocker, Matthias / Boxer, Matthew B / Schuchter, Lynn / Nathanson, Katherine L / Herlyn, Meenhard. ·Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA. · Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA. · Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. · Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA 90404, USA. · Helen F. Graham Cancer Center at Christiana Care, Newark, DE 19713, USA. · Ocular Oncology Service, Wills Eye Hospital, Philadelphia, PA 19107, USA. · Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107. · Department of Dermatology, University Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany; German Consortium of Translational Cancer Research, Heidelberg, Germany. · Lineberger Cancer Center, University of North Carolina Chapel Hill, NC 27514, USA. · Glaxosmithkline, Collegeville, PA 19426, USA. · Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. · Bayer Pharma AG, Berlin 13353, Germany. · National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA. · Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: herlynm@wistar.org. ·Cell Rep · Pubmed #29141225.

ABSTRACT: Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups.

17 Article Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines. 2017

Garman, Bradley / Anastopoulos, Ioannis N / Krepler, Clemens / Brafford, Patricia / Sproesser, Katrin / Jiang, Yuchao / Wubbenhorst, Bradley / Amaravadi, Ravi / Bennett, Joseph / Beqiri, Marilda / Elder, David / Flaherty, Keith T / Frederick, Dennie T / Gangadhar, Tara C / Guarino, Michael / Hoon, David / Karakousis, Giorgos / Liu, Qin / Mitra, Nandita / Petrelli, Nicholas J / Schuchter, Lynn / Shannan, Batool / Shields, Carol L / Wargo, Jennifer / Wenz, Brandon / Wilson, Melissa A / Xiao, Min / Xu, Wei / Xu, Xaiowei / Yin, Xiangfan / Zhang, Nancy R / Davies, Michael A / Herlyn, Meenhard / Nathanson, Katherine L. ·Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · The Wistar Institute, Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, Philadelphia, PA, USA. · Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA, USA. · Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Helen F. Graham Cancer Center at Christiana Care Health System, Newark, DE, USA. · Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Department of Medicine, Division of Hematology & Oncology, Massachusetts General Hospital, Boston, MA, USA. · Department of Translational Molecular Medicine, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA. · Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA. · Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Perlmutter Cancer Center, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA. · Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: knathans@upenn.edu. ·Cell Rep · Pubmed #29141224.

ABSTRACT: Tumor-sequencing studies have revealed the widespread genetic diversity of melanoma. Sequencing of 108 genes previously implicated in melanomagenesis was performed on 462 patient-derived xenografts (PDXs), cell lines, and tumors to identify mutational and copy number aberrations. Samples came from 371 unique individuals: 263 were naive to treatment, and 108 were previously treated with targeted therapy (34), immunotherapy (54), or both (20). Models of all previously reported major melanoma subtypes (BRAF, NRAS, NF1, KIT, and WT/WT/WT) were identified. Multiple minor melanoma subtypes were also recapitulated, including melanomas with multiple activating mutations in the MAPK-signaling pathway and chromatin-remodeling gene mutations. These well-characterized melanoma PDXs and cell lines can be used not only as reagents for a large array of biological studies but also as pre-clinical models to facilitate drug development.

18 Article P-REX1 amplification promotes progression of cutaneous melanoma via the PAK1/P38/MMP-2 pathway. 2017

Wang, Jinhua / Hirose, Hajime / Du, Guanhua / Chong, Kelly / Kiyohara, Eiji / Witz, Isaac P / Hoon, Dave S B. ·The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Target Research, Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. · Department of Translational Medicine, Division Molecular Oncology, John Wayne Cancer Institute (JWCI) at Providence Saint John's Health Center, Santa Monica, CA 90404, USA. · Department of Cell Research and Immunology, George S Wise, Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel. · Department of Translational Medicine, Division Molecular Oncology, John Wayne Cancer Institute (JWCI) at Providence Saint John's Health Center, Santa Monica, CA 90404, USA. Electronic address: hoond@jwci.org. ·Cancer Lett · Pubmed #28803992.

ABSTRACT: P-REX1 (PIP3-dependent Rac exchange factor-1) is a guanine nucleotide exchange factor that activates Rac by catalyzing exchange of GDP for GTP bound to Rac. Aberrant up-regulation of P-REX1 expression has a role in metastasis however, copy number (CN) and function of P-REX1 in cutaneous melanoma are unclear. To explore the role of P-REX1 in melanoma, SNP 6.0 and Exon 1.0 ST microarrays were assessed. There was a higher CN (2.82-fold change) of P-REX1 in melanoma cells than in melanocytes, and P-REX1 expression was significantly correlated with P-REX1 CN. When P-REX1 was knocked down in cells by P-REX1 shRNA, proliferation, colony formation, 3D matrigel growth, and migration/invasiveness were inhibited. Loss of P-REX1 inhibited cell proliferation by inhibiting cyclin D1, blocking cell cycle, and increased cell apoptosis by reducing expression of the protein survivin. Knockdown of P-REX1 expression inhibited cell migration/invasiveness by disrupting P-REX1/RAC1/PAK1/p38/MMP-2 pathway. Assessment of patient tumors and disease outcome demonstrated lower distant metastasis-free survival among AJCC stage I/II/III patients with high P-REX1 expression compared to patients with low P-REX1 expression. These results suggest P-REX1 plays an important role in tumor progression and a potential theranostic target.

19 Article NADPH oxidase 5 (NOX5)-induced reactive oxygen signaling modulates normoxic HIF-1α and p27 2017

Antony, Smitha / Jiang, Guojian / Wu, Yongzhong / Meitzler, Jennifer L / Makhlouf, Hala R / Haines, Diana C / Butcher, Donna / Hoon, Dave S / Ji, Jiuping / Zhang, Yiping / Juhasz, Agnes / Lu, Jiamo / Liu, Han / Dahan, Iris / Konate, Mariam / Roy, Krishnendu K / Doroshow, James H. ·Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland. · Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. · Pathology/Histotechnology Laboratory, Leidos Inc./Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland. · Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California. ·Mol Carcinog · Pubmed #28762556.

ABSTRACT: NADPH oxidase 5 (NOX5) generated reactive oxygen species (ROS) have been implicated in signaling cascades that regulate cancer cell proliferation. To evaluate and validate NOX5 expression in human tumors, we screened a broad range of tissue microarrays (TMAs), and report substantial overexpression of NOX5 in malignant melanoma and cancers of the prostate, breast, and ovary. In human UACC-257 melanoma cells that possesses high levels of functional endogenous NOX5, overexpression of NOX5 resulted in enhanced cell growth, increased numbers of BrdU positive cells, and increased γ-H2AX levels. Additionally, NOX5-overexpressing (stable and inducible) UACC-257 cells demonstrated increased normoxic HIF-1α expression and decreased p27

20 Article The RhoJ-BAD signaling network: An Achilles' heel for BRAF mutant melanomas. 2017

Ruiz, Rolando / Jahid, Sohail / Harris, Melissa / Marzese, Diego M / Espitia, Francisco / Vasudeva, Priya / Chen, Chi-Fen / de Feraudy, Sebastien / Wu, Jie / Gillen, Daniel L / Krasieva, Tatiana B / Tromberg, Bruce J / Pavan, William J / Hoon, Dave S / Ganesan, Anand K. ·Department of Biological Chemistry, University of California, Irvine, Irvine, CA, United States of America. · Department of Dermatology, University of California, Irvine, Irvine, CA, United States of America. · Department of Biology, The University of Alabama at Birmingham, Birmingham, AL, United States of America. · Department of Translational Molecular Medicine, Division Molecular Oncology, John Wayne Cancer Institute (JWCI), Providence Saint John's Health Center, Santa Monica, CA, United States of America. · Department of Statistics, University of California, Irvine, Irvine, CA, United States of America. · Laser Microbeam and Medical Program, Beckman Laser Institute, University of California, Irvine, Irvine, CA, United States of America. · National Human Genome Research Institute, National Institute of Health, Bethesda, MD, United States of America. ·PLoS Genet · Pubmed #28753606.

ABSTRACT: Genes and pathways that allow cells to cope with oncogene-induced stress represent selective cancer therapeutic targets that remain largely undiscovered. In this study, we identify a RhoJ signaling pathway that is a selective therapeutic target for BRAF mutant cells. RhoJ deletion in BRAF mutant melanocytes modulates the expression of the pro-apoptotic protein BAD as well as genes involved in cellular metabolism, impairing nevus formation, cellular transformation, and metastasis. Short-term treatment of nascent melanoma tumors with PAK inhibitors that block RhoJ signaling halts the growth of BRAF mutant melanoma tumors in vivo and induces apoptosis in melanoma cells in vitro via a BAD-dependent mechanism. As up to 50% of BRAF mutant human melanomas express high levels of RhoJ, these studies nominate the RhoJ-BAD signaling network as a therapeutic vulnerability for fledgling BRAF mutant human tumors.

21 Article MiR-200a Regulates CDK4/6 Inhibitor Effect by Targeting CDK6 in Metastatic Melanoma. 2017

Bustos, Matias A / Ono, Shigeshi / Marzese, Diego M / Oyama, Takashi / Iida, Yuuki / Cheung, Garrett / Nelson, Nellie / Hsu, Sandy C / Yu, Qiang / Hoon, Dave S B. ·Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA. · Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA. · Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA; Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA. · Cancer Biology and Pharmacology, Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore. · Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA; Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA. Electronic address: hoond@jwci.org. ·J Invest Dermatol · Pubmed #28526299.

ABSTRACT: The CDK4/6 pathway is frequently dysregulated in cutaneous melanoma. Recently, CDK4/6 inhibitors have shown promising clinical activity against several cancer types, including melanoma. Here, we show that microRNA-200a decreases CDK6 expression and thus reduces the response of CDK4/6 inhibitor in highly proliferative metastatic melanoma. Down-regulation of microRNA-200a expression in melanoma cells is associated with disease progression and a higher number of lymph node metastases. Furthermore, microRNA-200a expression is epigenetically modulated by both DNA methylation at the promoter region and chromatin accessibility of an upstream genomic region with enhancer activity. Mechanistically, overexpression of miR-200a in metastatic melanoma cells induces cell cycle arrest by targeting CDK6 and decreases the levels of phosphorylated-Rb1 and E2F-downstream targets, diminishing cell proliferation; these effects are recovered by CDK6 overexpression. Conversely, low microRNA-200a expression in metastatic melanoma cells results in higher levels of CDK6 and a more significant response to CDK4/6 inhibitors. We propose that microRNA-200a functions as a "cell cycle brake" that is lost during melanoma progression to metastasis and provides the ability to identify melanomas that are highly proliferative and more prompted to respond to CDK4/6 inhibitors.

22 Article CCR4 is a determinant of melanoma brain metastasis. 2017

Klein, Anat / Sagi-Assif, Orit / Meshel, Tsipi / Telerman, Alona / Izraely, Sivan / Ben-Menachem, Shlomit / Bayry, Jagadeesh / Marzese, Diego M / Ohe, Shuichi / Hoon, Dave S B / Erez, Neta / Witz, Isaac P. ·Department of Cell Research and Immunology, George S. Wise, Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel. · Inserm Unité 1138, Center de Recherche des Cordeliers, Université Pierre et Marie Curie, Université, Paris Descartes, Paris, France. · Department of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. · Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. ·Oncotarget · Pubmed #28415693.

ABSTRACT: We previously identified the chemokine receptor CCR4 as part of the molecular signature of melanoma brain metastasis. The aim of this study was to determine the functional significance of CCR4 in melanoma brain metastasis. We show that CCR4 is more highly expressed by brain metastasizing melanoma cells than by local cutaneous cells from the same melanoma. Moreover, we found that the expression of CCR4 is significantly higher in paired clinical specimens of melanoma metastases than in samples of primary tumors from the same patients. Notably, the expression of the CCR4 ligands, Ccl22 and Ccl17 is upregulated at the earliest stages of brain metastasis, and precedes the infiltration of melanoma cells to the brain. In-vitro, CCL17 induced migration and transendothelial migration of melanoma cells. Functionally, human melanoma cells over-expressing CCR4 were more tumorigenic and produced a higher load of spontaneous brain micrometastasis than control cells. Blocking CCR4 with a small molecule CCR4 antagonist in-vivo, reduced the tumorigenicity and micrometastasis formation of melanoma cells. Taken together, these findings implicate CCR4 as a driver of melanoma brain metastasis.

23 Article Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma. 2017

Iida, Yuuki / Ciechanover, Aaron / Marzese, Diego M / Hata, Keisuke / Bustos, Matias / Ono, Shigeshi / Wang, Jinhua / Salomon, Matthew P / Tran, Kevin / Lam, Stella / Hsu, Sandy / Nelson, Nellie / Kravtsova-Ivantsiv, Yelena / Mills, Gordon B / Davies, Michael A / Hoon, Dave S B. ·Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California. · The David and Janet Polak Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Bat-Galim, Haifa, Israel. · John Wayne Cancer Institute Genome Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California. · Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California. hoond@jwci.org. ·Clin Cancer Res · Pubmed #28389511.

ABSTRACT:

24 Article ATR Mutations Promote the Growth of Melanoma Tumors by Modulating the Immune Microenvironment. 2017

Chen, Chi-Fen / Ruiz-Vega, Rolando / Vasudeva, Priya / Espitia, Francisco / Krasieva, Tatiana B / de Feraudy, Sebastien / Tromberg, Bruce J / Huang, Sharon / Garner, Chad P / Wu, Jie / Hoon, Dave S / Ganesan, Anand K. ·Department of Dermatology, University of California, Irvine, Irvine, CA 92697, USA. · Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA. · Laser Microbeam and Medical Program, Beckman Laser Institute, University of California, Irvine, Irvine, CA 92697, USA. · Department of Molecular Oncology, John Wayne Cancer Institute (JWCI), Providence Saint John's Health Center, Santa Monica, CA 90404, USA. · Department of Epidemiology, University of California, Irvine, Irvine, CA 92697, USA. · Department of Dermatology, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: aganesan@uci.edu. ·Cell Rep · Pubmed #28273450.

ABSTRACT: Melanomas accumulate a high burden of mutations that could potentially generate neoantigens, yet somehow suppress the immune response to facilitate continued growth. In this study, we identify a subset of human melanomas that have loss-of-function mutations in ATR, a kinase that recognizes and repairs UV-induced DNA damage and is required for cellular proliferation. ATR mutant tumors exhibit both the accumulation of multiple mutations and the altered expression of inflammatory genes, resulting in decreased T cell recruitment and increased recruitment of macrophages known to spur tumor invasion. Taken together, these studies identify a mechanism by which melanoma cells modulate the immune microenvironment to promote continued growth.

25 Article The Impact of Smoking on Sentinel Node Metastasis of Primary Cutaneous Melanoma. 2017

Jones, Maris S / Jones, Peter C / Stern, Stacey L / Elashoff, David / Hoon, Dave S B / Thompson, John / Mozzillo, Nicola / Nieweg, Omgo E / Noyes, Dirk / Hoekstra, Harald J / Zager, Jonathan S / Roses, Daniel F / Testori, Alessandro / Coventry, Brendon J / Smithers, Mark B / Andtbacka, Robert / Agnese, Doreen / Schultz, Erwin / Hsueh, Eddy C / Kelley, Mark / Schneebaum, Schlomo / Jacobs, Lisa / Bowles, Tawnya / Kashani-Sabet, Mohammed / Johnson, Douglas / Faries, Mark B. ·Division of Surgical Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. · Department of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. · Department of Biostatistics, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. · UCLA Department of Biostatistics, Los Angeles, CA, USA. · Melanoma Institute Australia, Sydney, NSW, Australia. · Istituto Nazionale dei Tumori Napoli, Napoli, Italy. · IHC Cancer Services, Intermountain Medical Center, Salt Lake City, UT, USA. · Universitair Medisch Centrum Groningen, Groningen, The Netherlands. · H. Lee Moffitt Cancer Center, Tampa, USA. · NYU Langone Medical Center, New York, USA. · Istituto Europeo di Oncologia, Milano, Italy. · Royal Adelaide Hospital Discipline of Surgery, Royal Adelaide HospitalUniversity of Adelaide, Adelaide, SA, Australia. · Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. · Huntsman Cancer Institute, Salt Lake City, USA. · Ohio State University, Columbus, USA. · Nuremberg General Hospital - Paracelsus Medical University, Nuremberg, Germany. · Saint Louis University, St. Louis, USA. · Vanderbilt University, Nashville, USA. · Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel. · Johns Hopkins Medical Institute, Baltimore, USA. · California Pacific Medical Center, San Francisco, USA. · Department of Melanoma Research, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. mark.faries@jwci.org. ·Ann Surg Oncol · Pubmed #28224364.

ABSTRACT: BACKGROUND: Although a well-established causative relationship exists between smoking and several epithelial cancers, the association of smoking with metastatic progression in melanoma is not well studied. We hypothesized that smokers would be at increased risk for melanoma metastasis as assessed by sentinel lymph node (SLN) biopsy. METHODS: Data from the first international Multicenter Selective Lymphadenectomy Trial (MSLT-I) and the screening-phase of the second trial (MSLT-II) were analyzed to determine the association of smoking with clinicopathologic variables and SLN metastasis. RESULTS: Current smoking was strongly associated with SLN metastasis (p = 0.004), even after adjusting for other predictors of metastasis. Among 4231 patients (1025 in MSLT-I and 3206 in MSLT-II), current or former smoking was also independently associated with ulceration (p < 0.001 and p < 0.001, respectively). Compared with current smoking, never smoking was independently associated with decreased Breslow thickness in multivariate analysis (p = 0.002) and with a 0.25 mm predicted decrease in thickness. CONCLUSION: The direct correlation between current smoking and SLN metastasis of primary cutaneous melanoma was independent of its correlation with tumor thickness and ulceration. Smoking cessation should be strongly encouraged among patients with or at risk for melanoma.

Next