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Breast Neoplasms: HELP
Articles by Nicola Aceto
Based on 17 articles published since 2010
(Why 17 articles?)
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Between 2010 and 2020, N. Aceto wrote the following 17 articles about Breast Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial Memo is a copper-dependent redox protein with an essential role in migration and metastasis. 2014

MacDonald, Gwen / Nalvarte, Ivan / Smirnova, Tatiana / Vecchi, Manuela / Aceto, Nicola / Dolemeyer, Arno / Frei, Anna / Lienhard, Susanne / Wyckoff, Jeffrey / Hess, Daniel / Seebacher, Jan / Keusch, Jeremy J / Gut, Heinz / Salaun, Daniele / Mazzarol, Giovanni / Disalvatore, Davide / Bentires-Alj, Mohamed / Di Fiore, Pier Paolo / Badache, Ali / Hynes, Nancy E. ·Friedrich Miescher Institute for Biomedical Research, Basel 4058, Switzerland. · IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan 20139, Italy. Molecular Medicine Program, Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy. · Friedrich Miescher Institute for Biomedical Research, Basel 4058, Switzerland. University of Basel, Basel 4002, Switzerland. · Novartis Institutes for BioMedical Research, Basel 4057, Switzerland. · Centre de Recherche en Cancérologie de Marseille, Inserm (U1068), Institut Paoli-Calmettes, Aix-Marseille Université, Centre National de la Recherche Scientifique (UMR7258), Marseille 13009, France. · Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan 20141, Italy. · Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan 20141, Italy. · IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan 20139, Italy. Molecular Medicine Program, Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy. Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan 20122, Italy. · Friedrich Miescher Institute for Biomedical Research, Basel 4058, Switzerland. University of Basel, Basel 4002, Switzerland. nancy.hynes@fmi.ch. ·Sci Signal · Pubmed #24917593.

ABSTRACT: Memo is an evolutionarily conserved protein with a critical role in cell motility. We found that Memo was required for migration and invasion of breast cancer cells in vitro and spontaneous lung metastasis from breast cancer cell xenografts in vivo. Biochemical assays revealed that Memo is a copper-dependent redox enzyme that promoted a more oxidized intracellular milieu and stimulated the production of reactive oxygen species (ROS) in cellular structures involved in migration. Memo was also required for the sustained production of the ROS O2- by NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 1 (NOX1) in breast cancer cells. Memo abundance was increased in >40% of the primary breast tumors tested, was correlated with clinical parameters of aggressive disease, and was an independent prognostic factor of early distant metastasis.

2 Article Endothelial cell-derived nidogen-1 inhibits migration of SK-BR-3 breast cancer cells. 2019

Ferraro, Daniela A / Patella, Francesca / Zanivan, Sara / Donato, Cinzia / Aceto, Nicola / Giannotta, Monica / Dejana, Elisabetta / Diepenbruck, Maren / Christofori, Gerhard / Buess, Martin. ·Tumor Biology, Department of Biomedicine, University of Basel, 4058, Basel, Switzerland. · Tumour Microenvironment and Proteomics, Cancer Research UK Beatson Institute, Glasgow, G611BD, UK. · Cancer Metastasis, Department of Biomedicine, University of Basel, 4058, Basel, Switzerland. · Vascular Biology Unit, FIRC Institute of Molecular Oncology, 20139, Milan, Italy. · Department of Oncology, St. Claraspital, Kleinriehenstrasse 30, 4016, Basel, Switzerland. martin.buess@claraspital.ch. ·BMC Cancer · Pubmed #30947697.

ABSTRACT: BACKGROUND: The tumour microenvironment is a critical regulator of malignant cancer progression. While endothelial cells have been widely studied in the context of tumour angiogenesis, their role as modulators of cancer cell invasion and migration is poorly understood. METHODS: We have investigated the influence of endothelial cells on the invasive and migratory behaviour of human cancer cells in vitro. RESULTS: Upon exposure to culture supernatants of endothelial cells, distinct cancer cells, such as SK-BR-3 cells, showed significantly increased invasion and cell migration concomitant with changes in cell morphology and gene expression reminiscent of an epithelial-mesenchymal transition (EMT). Interestingly, the pro-migratory effect on SK-BR-3 cells was significantly enhanced by supernatants obtained from subconfluent, proliferative endothelial cells rather than from confluent, quiescent endothelial cells. Systematically comparing the supernatants of subconfluent and confluent endothelial cells by quantitative MS proteomics revealed eight candidate proteins that were secreted at significantly higher levels by confluent endothelial cells representing potential inhibitors of cancer cell migration. Among these proteins, nidogen-1 was exclusively expressed in confluent endothelial cells and was found to be necessary and sufficient for the inhibition of SK-BR-3 cell migration. Indeed, SK-BR-3 cells exposed to nidogen-1-depleted endothelial supernatants showed increased promigratory STAT3 phosphorylation along with increased cell migration. This reflects the situation of enhanced SK-BR-3 migration upon stimulation with conditioned medium from subconfluent endothelial cells with inherent absence of nidogen-1 expression. CONCLUSION: The identification of nidogen-1 as an endothelial-derived inhibitor of migration of distinct cancer cell types reveals a novel mechanism of endothelial control over cancer progression.

3 Article Neutrophils escort circulating tumour cells to enable cell cycle progression. 2019

Szczerba, Barbara Maria / Castro-Giner, Francesc / Vetter, Marcus / Krol, Ilona / Gkountela, Sofia / Landin, Julia / Scheidmann, Manuel C / Donato, Cinzia / Scherrer, Ramona / Singer, Jochen / Beisel, Christian / Kurzeder, Christian / Heinzelmann-Schwarz, Viola / Rochlitz, Christoph / Weber, Walter Paul / Beerenwinkel, Niko / Aceto, Nicola. ·Department of Biomedicine, Cancer Metastasis Lab, University of Basel and University Hospital Basel, Basel, Switzerland. · SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. · Gynecologic Cancer Center, University Hospital Basel, Basel, Switzerland. · Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. · Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. · Breast Center, University of Basel and University Hospital Basel, Basel, Switzerland. · Department of Biomedicine, Cancer Metastasis Lab, University of Basel and University Hospital Basel, Basel, Switzerland. Nicola.Aceto@unibas.ch. ·Nature · Pubmed #30728496.

ABSTRACT: A better understanding of the features that define the interaction between cancer cells and immune cells is important for the development of new cancer therapies

4 Article Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding. 2019

Gkountela, Sofia / Castro-Giner, Francesc / Szczerba, Barbara Maria / Vetter, Marcus / Landin, Julia / Scherrer, Ramona / Krol, Ilona / Scheidmann, Manuel C / Beisel, Christian / Stirnimann, Christian U / Kurzeder, Christian / Heinzelmann-Schwarz, Viola / Rochlitz, Christoph / Weber, Walter Paul / Aceto, Nicola. ·Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland. · Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland; SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland. · Gynecologic Cancer Center, University Hospital Basel, 4056 Basel, Switzerland; Department of Medical Oncology, University Hospital Basel, 4056 Basel, Switzerland. · Department of Medical Oncology, University Hospital Basel, 4056 Basel, Switzerland; Breast Center, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. · Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland. · NEXUS Personalized Health Technologies, ETH Zurich, 8092 Zurich, Switzerland. · Gynecologic Cancer Center, University Hospital Basel, 4056 Basel, Switzerland; Breast Center, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. · Gynecologic Cancer Center, University Hospital Basel, 4056 Basel, Switzerland. · Department of Medical Oncology, University Hospital Basel, 4056 Basel, Switzerland. · Breast Center, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. · Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland. Electronic address: nicola.aceto@unibas.ch. ·Cell · Pubmed #30633912.

ABSTRACT: The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na

5 Article Denosumab treatment is associated with the absence of circulating tumor cells in patients with breast cancer. 2018

Vetter, Marcus / Landin, Julia / Szczerba, Barbara Maria / Castro-Giner, Francesc / Gkountela, Sofia / Donato, Cinzia / Krol, Ilona / Scherrer, Ramona / Balmelli, Catharina / Malinovska, Alexandra / Zippelius, Alfred / Kurzeder, Christian / Heinzelmann-Schwarz, Viola / Weber, Walter Paul / Rochlitz, Christoph / Aceto, Nicola. ·Gynecologic Cancer Center, University Hospital Basel, 4056, Basel, Switzerland. · Department of Medical Oncology, University Hospital Basel, 4056, Basel, Switzerland. · Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Mattenstrasse 28, CH-4058, Basel, Switzerland. · SIB Swiss Institute of Bioinformatics, 1015, Lausanne, Switzerland. · Breast Center, University Hospital Basel, 4056, Basel, Switzerland. · Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Mattenstrasse 28, CH-4058, Basel, Switzerland. nicola.aceto@unibas.ch. ·Breast Cancer Res · Pubmed #30458879.

ABSTRACT: BACKGROUND: The presence of circulating tumor cells (CTCs) in patients with breast cancer correlates to a bad prognosis. Yet, CTCs are detectable in only a minority of patients with progressive breast cancer, and factors that influence the abundance of CTCs remain elusive. METHODS: We conducted CTC isolation and enumeration in a selected group of 73 consecutive patients characterized by progressive invasive breast cancer, high tumor load and treatment discontinuation at the time of CTC isolation. CTCs were quantified with the Parsortix microfluidic device. Clinicopathological variables, blood counts at the time of CTC isolation and detailed treatment history prior to blood sampling were evaluated for each patient. RESULTS: Among 73 patients, we detected at least one CTC per 7.5 ml of blood in 34 (46%). Of these, 22 (65%) had single CTCs only, whereas 12 (35%) featured both single CTCs and CTC clusters. Treatment with the monoclonal antibody denosumab correlated with the absence of CTCs, both when considering all patients and when considering only those with bone metastasis. We also found that low red blood cell count was associated with the presence of CTCs, whereas high CA 15-3 tumor marker, high mean corpuscular volume, high white blood cell count and high mean platelet volume associated specifically with CTC clusters. CONCLUSIONS: In addition to blood count correlatives to single and clustered CTCs, we found that denosumab treatment associates with most patients lacking CTCs from their peripheral circulation. Prospective studies will be needed to validate the involvement of denosumab in the prevention of CTC generation.

6 Article AR Expression in Breast Cancer CTCs Associates with Bone Metastases. 2018

Aceto, Nicola / Bardia, Aditya / Wittner, Ben S / Donaldson, Maria C / O'Keefe, Ryan / Engstrom, Amanda / Bersani, Francesca / Zheng, Yu / Comaills, Valentine / Niederhoffer, Kira / Zhu, Huili / Mackenzie, Olivia / Shioda, Toshi / Sgroi, Dennis / Kapur, Ravi / Ting, David T / Moy, Beverly / Ramaswamy, Sridhar / Toner, Mehmet / Haber, Daniel A / Maheswaran, Shyamala. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. · Department of Medicine, Harvard Medical School, Boston, Massachusetts. · Department of Pathology, Harvard Medical School, Boston, Massachusetts. · Center for Bioengineering in Medicine, Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Harvard Medical School, Boston, Massachusetts. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. dhaber@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu. · Howard Hughes Medical Institute, Chevy Chase, Maryland. ·Mol Cancer Res · Pubmed #29453314.

ABSTRACT: Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing was performed of circulating tumor cells (CTC) isolated from blood samples of women with metastatic estrogen receptor (ER)

7 Article Microfluidic isolation of platelet-covered circulating tumor cells. 2017

Jiang, Xiaocheng / Wong, Keith H K / Khankhel, Aimal H / Zeinali, Mahnaz / Reategui, Eduardo / Phillips, Matthew J / Luo, Xi / Aceto, Nicola / Fachin, Fabio / Hoang, Anh N / Kim, Wooseok / Jensen, Annie E / Sequist, Lecia V / Maheswaran, Shyamala / Haber, Daniel A / Stott, Shannon L / Toner, Mehmet. ·Center for Engineering in Medicine, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA. sstott@mgh.harvard.edu mtoner@mgh.harvard.edu. ·Lab Chip · Pubmed #28932842.

ABSTRACT: The interplay between platelets and tumor cells is known to play important roles in metastasis by enhancing tumor cell survival, tumor-vascular interactions, and escape from immune surveillance. However, platelet-covered circulating tumor cells (CTC) are extremely difficult to isolate due to masking or downregulation of surface epitopes. Here we describe a microfluidic platform that takes advantage of the satellite platelets on the surface of these "stealth" CTCs as a ubiquitous surface marker for isolation. Compared to conventional CTC enrichment techniques which rely on known surface markers expressed by tumor cells, platelet-targeted isolation is generally applicable to CTCs of both epithelial and mesenchymal phenotypes. Our approach first depletes unbound, free platelets by means of hydrodynamic size-based sorting, followed by immunoaffinity-based capture of platelet-covered CTCs using a herringbone micromixing device. This method enabled the reliable isolation of CTCs from 66% of lung and 60% of breast cancer (both epithelial) patient samples, as well as in 83% of melanoma (mesenchymal) samples. Interestingly, we observed special populations of CTCs that were extensively covered by platelets, as well as CTC-leukocyte clusters. Because these cloaked CTCs often escape conventional positive and negative isolation mechanisms, further characterization of these cells may uncover important yet overlooked biological information in blood-borne metastasis and cancer immunology.

8 Article Genomic Instability Is Induced by Persistent Proliferation of Cells Undergoing Epithelial-to-Mesenchymal Transition. 2016

Comaills, Valentine / Kabeche, Lilian / Morris, Robert / Buisson, Rémi / Yu, Min / Madden, Marissa Wells / LiCausi, Joseph A / Boukhali, Myriam / Tajima, Ken / Pan, Shiwei / Aceto, Nicola / Sil, Srinjoy / Zheng, Yu / Sundaresan, Tilak / Yae, Toshifumi / Jordan, Nicole Vincent / Miyamoto, David T / Ting, David T / Ramaswamy, Sridhar / Haas, Wilhelm / Zou, Lee / Haber, Daniel A / Maheswaran, Shyamala. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Harvard Medical School, Charlestown, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: maheswaran@helix.mgh.harvard.edu. ·Cell Rep · Pubmed #27926867.

ABSTRACT: TGF-β secreted by tumor stroma induces epithelial-to-mesenchymal transition (EMT) in cancer cells, a reversible phenotype linked to cancer progression and drug resistance. However, exposure to stromal signals may also lead to heritable changes in cancer cells, which are poorly understood. We show that epithelial cells failing to undergo proliferation arrest during TGF-β-induced EMT sustain mitotic abnormalities due to failed cytokinesis, resulting in aneuploidy. This genomic instability is associated with the suppression of multiple nuclear envelope proteins implicated in mitotic regulation and is phenocopied by modulating the expression of LaminB1. While TGF-β-induced mitotic defects in proliferating cells are reversible upon its withdrawal, the acquired genomic abnormalities persist, leading to increased tumorigenic phenotypes. In metastatic breast cancer patients, increased mesenchymal marker expression within single circulating tumor cells is correlated with genomic instability. These observations identify a mechanism whereby microenvironment-derived signals trigger heritable genetic changes within cancer cells, contributing to tumor evolution.

9 Article A microfluidic device for label-free, physical capture of circulating tumor cell clusters. 2015

Sarioglu, A Fatih / Aceto, Nicola / Kojic, Nikola / Donaldson, Maria C / Zeinali, Mahnaz / Hamza, Bashar / Engstrom, Amanda / Zhu, Huili / Sundaresan, Tilak K / Miyamoto, David T / Luo, Xi / Bardia, Aditya / Wittner, Ben S / Ramaswamy, Sridhar / Shioda, Toshi / Ting, David T / Stott, Shannon L / Kapur, Ravi / Maheswaran, Shyamala / Haber, Daniel A / Toner, Mehmet. ·1] Center for Engineering in Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. · 1] Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. · 1] Center for Engineering in Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. · 1] Center for Engineering in Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Center for Engineering in Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. · 1] Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. · 1] Center for Engineering in Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. · 1] Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. · 1] Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. ·Nat Methods · Pubmed #25984697.

ABSTRACT: Cancer cells metastasize through the bloodstream either as single migratory circulating tumor cells (CTCs) or as multicellular groupings (CTC clusters). Existing technologies for CTC enrichment are designed to isolate single CTCs, and although CTC clusters are detectable in some cases, their true prevalence and significance remain to be determined. Here we developed a microchip technology (the Cluster-Chip) to capture CTC clusters independently of tumor-specific markers from unprocessed blood. CTC clusters are isolated through specialized bifurcating traps under low-shear stress conditions that preserve their integrity, and even two-cell clusters are captured efficiently. Using the Cluster-Chip, we identified CTC clusters in 30-40% of patients with metastatic breast or prostate cancer or with melanoma. RNA sequencing of CTC clusters confirmed their tumor origin and identified tissue-derived macrophages within the clusters. Efficient capture of CTC clusters will enable the detailed characterization of their biological properties and role in metastasis.

10 Article Tunable nanostructured coating for the capture and selective release of viable circulating tumor cells. 2015

Reátegui, Eduardo / Aceto, Nicola / Lim, Eugene J / Sullivan, James P / Jensen, Anne E / Zeinali, Mahnaz / Martel, Joseph M / Aranyosi, Alexander J / Li, Wei / Castleberry, Steven / Bardia, Aditya / Sequist, Lecia V / Haber, Daniel A / Maheswaran, Shyamala / Hammond, Paula T / Toner, Mehmet / Stott, Shannon L. ·Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Building 114, 16th Street, Charlestown, MA, 02129, USA; Shriners Hospital for Children, Harvard Medical School, 51 Blossom Street, Boston, MA, 02114, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School 55, 55 Fruit Street, Boston, MA, 02114, USA. ·Adv Mater · Pubmed #25640006.

ABSTRACT: A layer-by-layer gelatin nanocoating is presented for use as a tunable, dual response biomaterial for the capture and release of circulating tumor cells (CTCs) from cancer patient blood. The entire nanocoating can be dissolved from the surface of microfluidic devices through biologically compatible temperature shifts. Alternatively, individual CTCs can be released through locally applied mechanical stress.

11 Article Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases. 2015

Sausgruber, N / Coissieux, M-M / Britschgi, A / Wyckoff, J / Aceto, N / Leroy, C / Stadler, M B / Voshol, H / Bonenfant, D / Bentires-Alj, M. ·Mechanisms of cancer, Friedrich Miescher Institute (FMI) for Biomedical Research, Basel, Switzerland. · 1] Mechanisms of cancer, Friedrich Miescher Institute (FMI) for Biomedical Research, Basel, Switzerland [2] Koch Institute for Integrated Cancer Research, Massachusetts Institute for Technology, Cambridge, MA, USA. · 1] Mechanisms of cancer, Friedrich Miescher Institute (FMI) for Biomedical Research, Basel, Switzerland [2] Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. · 1] Mechanisms of cancer, Friedrich Miescher Institute (FMI) for Biomedical Research, Basel, Switzerland [2] Analytical sciences and Imaging, Novartis Institutes for Biomedical Research, Basel, Switzerland. · 1] Mechanisms of cancer, Friedrich Miescher Institute (FMI) for Biomedical Research, Basel, Switzerland [2] Swiss Institute of Bioinformatics, Basel, Switzerland. · Analytical sciences and Imaging, Novartis Institutes for Biomedical Research, Basel, Switzerland. ·Oncogene · Pubmed #24931162.

ABSTRACT: Tumor cell migration has a fundamental role in early steps of metastasis, the fatal hallmark of cancer. In the present study, we investigated the effects of the tyrosine phosphatase, SRC-homology 2 domain-containing phosphatase 2 (SHP2), on cell migration in metastatic triple-negative breast cancer (TNBC), an aggressive disease associated with a poor prognosis for which a targeted therapy is not yet available. Using mouse models and multiphoton intravital imaging, we have identified a crucial effect of SHP2 on TNBC cell motility in vivo. Further, analysis of TNBC cells revealed that SHP2 also influences cell migration, chemotaxis and invasion in vitro. Unbiased phosphoproteomics and biochemical analysis showed that SHP2 activates several SRC-family kinases and downstream targets, most of which are inducers of migration and invasion. In particular, direct interaction between SHP2 and c-SRC was revealed by a fluorescence resonance energy transfer assay. These results suggest that SHP2 is a crucial factor during early steps of TNBC migration to distant organs.

12 Article Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. 2014

Aceto, Nicola / Bardia, Aditya / Miyamoto, David T / Donaldson, Maria C / Wittner, Ben S / Spencer, Joel A / Yu, Min / Pely, Adam / Engstrom, Amanda / Zhu, Huili / Brannigan, Brian W / Kapur, Ravi / Stott, Shannon L / Shioda, Toshi / Ramaswamy, Sridhar / Ting, David T / Lin, Charles P / Toner, Mehmet / Haber, Daniel A / Maheswaran, Shyamala. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA. · Advanced Microscopy Program, Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA. · Center for Bioengineering in Medicine, Harvard Medical School, Boston, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA; Center for Bioengineering in Medicine, Harvard Medical School, Boston, MA 02129, USA. · Center for Bioengineering in Medicine, Harvard Medical School, Boston, MA 02129, USA; Department of Surgery, Harvard Medical School, Boston, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: dhaber@mgh.harvard.edu. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Surgery, Harvard Medical School, Boston, MA 02129, USA. Electronic address: maheswaran@helix.mgh.harvard.edu. ·Cell · Pubmed #25171411.

ABSTRACT: Circulating tumor cell clusters (CTC clusters) are present in the blood of patients with cancer but their contribution to metastasis is not well defined. Using mouse models with tagged mammary tumors, we demonstrate that CTC clusters arise from oligoclonal tumor cell groupings and not from intravascular aggregation events. Although rare in the circulation compared with single CTCs, CTC clusters have 23- to 50-fold increased metastatic potential. In patients with breast cancer, single-cell resolution RNA sequencing of CTC clusters and single CTCs, matched within individual blood samples, identifies the cell junction component plakoglobin as highly differentially expressed. In mouse models, knockdown of plakoglobin abrogates CTC cluster formation and suppresses lung metastases. In breast cancer patients, both abundance of CTC clusters and high tumor plakoglobin levels denote adverse outcomes. Thus, CTC clusters are derived from multicellular groupings of primary tumor cells held together through plakoglobin-dependent intercellular adhesion, and though rare, they greatly contribute to the metastatic spread of cancer.

13 Article Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. 2014

Yu, Min / Bardia, Aditya / Aceto, Nicola / Bersani, Francesca / Madden, Marissa W / Donaldson, Maria C / Desai, Rushil / Zhu, Huili / Comaills, Valentine / Zheng, Zongli / Wittner, Ben S / Stojanov, Petar / Brachtel, Elena / Sgroi, Dennis / Kapur, Ravi / Shioda, Toshihiro / Ting, David T / Ramaswamy, Sridhar / Getz, Gad / Iafrate, A John / Benes, Cyril / Toner, Mehmet / Maheswaran, Shyamala / Haber, Daniel A. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA. Department of Medical Epidemiology and Biostatistics, Karolinska Insitutet, Stockholm, Sweden. · Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. · Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA. · Center for Bioengineering in Medicine, Harvard Medical School, Charlestown, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. · Center for Bioengineering in Medicine, Harvard Medical School, Charlestown, MA 02129, USA. Department of Surgery, Harvard Medical School, Charlestown, MA 02129, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Surgery, Harvard Medical School, Charlestown, MA 02129, USA. maheswaran@helix.mgh.harvard.edu haber@helix.mgh.harvard.edu. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA. maheswaran@helix.mgh.harvard.edu haber@helix.mgh.harvard.edu. ·Science · Pubmed #25013076.

ABSTRACT: Circulating tumor cells (CTCs) are present at low concentrations in the peripheral blood of patients with solid tumors. It has been proposed that the isolation, ex vivo culture, and characterization of CTCs may provide an opportunity to noninvasively monitor the changing patterns of drug susceptibility in individual patients as their tumors acquire new mutations. In a proof-of-concept study, we established CTC cultures from six patients with estrogen receptor-positive breast cancer. Three of five CTC lines tested were tumorigenic in mice. Genome sequencing of the CTC lines revealed preexisting mutations in the PIK3CA gene and newly acquired mutations in the estrogen receptor gene (ESR1), PIK3CA gene, and fibroblast growth factor receptor gene (FGFR2), among others. Drug sensitivity testing of CTC lines with multiple mutations revealed potential new therapeutic targets. With optimization of CTC culture conditions, this strategy may help identify the best therapies for individual cancer patients over the course of their disease.

14 Article Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer. 2014

Tao, Jessica J / Castel, Pau / Radosevic-Robin, Nina / Elkabets, Moshe / Auricchio, Neil / Aceto, Nicola / Weitsman, Gregory / Barber, Paul / Vojnovic, Borivoj / Ellis, Haley / Morse, Natasha / Viola-Villegas, Nerissa Therese / Bosch, Ana / Juric, Dejan / Hazra, Saswati / Singh, Sharat / Kim, Phillip / Bergamaschi, Anna / Maheswaran, Shyamala / Ng, Tony / Penault-Llorca, Frédérique / Lewis, Jason S / Carey, Lisa A / Perou, Charles M / Baselga, José / Scaltriti, Maurizio. ·1Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA. ·Sci Signal · Pubmed #24667376.

ABSTRACT: Both abundant epidermal growth factor receptor (EGFR or ErbB1) and high activity of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway are common and therapeutically targeted in triple-negative breast cancer (TNBC). However, activation of another EGFR family member [human epidermal growth factor receptor 3 (HER3) (or ErbB3)] may limit the antitumor effects of these drugs. We found that TNBC cell lines cultured with the EGFR or HER3 ligand EGF or heregulin, respectively, and treated with either an Akt inhibitor (GDC-0068) or a PI3K inhibitor (GDC-0941) had increased abundance and phosphorylation of HER3. The phosphorylation of HER3 and EGFR in response to these treatments was reduced by the addition of a dual EGFR and HER3 inhibitor (MEHD7945A). MEHD7945A also decreased the phosphorylation (and activation) of EGFR and HER3 and the phosphorylation of downstream targets that occurred in response to the combination of EGFR ligands and PI3K-Akt pathway inhibitors. In culture, inhibition of the PI3K-Akt pathway combined with either MEHD7945A or knockdown of HER3 decreased cell proliferation compared with inhibition of the PI3K-Akt pathway alone. Combining either GDC-0068 or GDC-0941 with MEHD7945A inhibited the growth of xenografts derived from TNBC cell lines or from TNBC patient tumors, and this combination treatment was also more effective than combining either GDC-0068 or GDC-0941 with cetuximab, an EGFR-targeted antibody. After therapy with EGFR-targeted antibodies, some patients had residual tumors with increased HER3 abundance and EGFR/HER3 dimerization (an activating interaction). Thus, we propose that concomitant blockade of EGFR, HER3, and the PI3K-Akt pathway in TNBC should be investigated in the clinical setting.

15 Article Tyrosine phosphatase PTPα contributes to HER2-evoked breast tumor initiation and maintenance. 2014

Meyer, D S / Aceto, N / Sausgruber, N / Brinkhaus, H / Müller, U / Pallen, C J / Bentires-Alj, M. ·Mechanisms of cancer, Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland. · Department of Pediatrics and Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada. ·Oncogene · Pubmed #23318421.

ABSTRACT: Protein tyrosine phosphatase alpha (PTPα/PTPRA) was shown previously to be overexpressed in human primary breast cancers, and to suppress apoptosis in estrogen receptor-negative breast cancer cells in vitro. However, it is not known whether PTPα is important for mammary tumor initiation, maintenance and/or progression. We have used a combination of three-dimensional cultures, a transgenic mouse model of breast cancer lacking PTPα as well as xenografts of human breast cancer cell lines to address these questions. We found that PTPα knockdown after overt tumor development reduced the growth of HER2-positive human breast cancer cell lines, and that this effect was accompanied by a reduction in AKT phosphorylation. However, PTPα knockdown did not affect invasiveness of HER2-positive human breast cancer cells grown in three-dimensional cultures. Moreover, in MMTV-NeuNT/PTPα(-/-) mice, PTPα ablation did not affect NeuNT-evoked tumor onset or metastasis but decreased the number of tumors per mouse. Thus, we demonstrate that PTPα contributes to both HER2/Neu-mediated mammary tumor initiation and maintenance. Our results suggest that inhibition of PTPα can have a beneficial effect on HER2-positive breast cancers, but that inhibition of additional targets is needed to block breast tumorigenesis.

16 Article Mammary tumor formation and metastasis evoked by a HER2 splice variant. 2013

Alajati, Abdullah / Sausgruber, Nina / Aceto, Nicola / Duss, Stephan / Sarret, Sophie / Voshol, Hans / Bonenfant, Debora / Bentires-Alj, Mohamed. ·Friedrich Miescher Institute for Biomedical Research, Maulbeerstr. 66, Basel, CH 4058, Switzerland. ·Cancer Res · Pubmed #23867476.

ABSTRACT: The HER2 gene is amplified and overexpressed in approximately 20% of invasive breast cancers where it is associated with metastasis and poor prognosis. Here, we describe a constitutively active splice variant of HER2 (Delta-HER2) in human mammary epithelial cells that evokes aggressive breast cancer phenotypes. Delta-HER2 overexpression in mammary epithelial cells was sufficient to reduce apoptosis, increase proliferation, and induce expression of mesenchymal markers, features that were associated with greater invasive potential in three-dimensional cultures in vitro and more aggressive tumorigenicity and metastasis in vivo. In contrast, overexpression of wild-type HER2 was insufficient at evoking such effects. Unbiased protein-tyrosine phosphorylation profiling in Delta-HER2-expressing cells revealed increased phosphorylation of several signaling proteins not previously known to be controlled by the HER2 pathway. Furthermore, microarray expression analysis revealed activation of genes known to be highly expressed in ER-negative, high-grade, and metastatic primary breast tumors. Together, our results provide mechanistic insights into the activity of a highly pathogenic splice variant of HER2.

17 Article Co-expression of HER2 and HER3 receptor tyrosine kinases enhances invasion of breast cells via stimulation of interleukin-8 autocrine secretion. 2012

Aceto, Nicola / Duss, Stephan / MacDonald, Gwen / Meyer, Dominique S / Roloff, Tim-C / Hynes, Nancy E / Bentires-Alj, Mohamed. · ·Breast Cancer Res · Pubmed #23062209.

ABSTRACT: INTRODUCTION: The tyrosine kinase receptors HER2 and HER3 play an important role in breast cancer. The HER2/HER3 heterodimer is a critical oncogenic unit associated with reduced relapse-free and decreased overall survival. While signaling cascades downstream of HER2 and HER3 have been studied extensively at the level of post-translational modification, little is known about the effects of HER2/HER3 overexpression and activation on gene expression in breast cancer. We have now defined the genetic landscape induced by activation of the HER2/HER3 unit in mammary cells, and have identified interleukin (IL)8 and CXCR1 as potential therapeutic targets for the treatment of HER2/HER3-overexpressing breast cancers. METHODS: Three-dimensional (3D) cultures, invasion and migration assays were used to determine the effects of HER2 and HER3 co-expression and activation. Gene expression analysis was performed to identify the gene network induced by HER2/HER3 in 3D cultures. Bioinformatic analysis and neutralizing antibodies were used to identify key mediators of HER2/HER3-evoked invasion. RESULTS: Co-expression of the tyrosine kinase receptors HER2 and HER3 induced migration and invasion of MCF10A cells. Microarray analysis of these cells revealed a specific "HER2/HER3 signature" comprising 80 upregulated transcripts, with IL8 being the highest (11-fold upregulation). Notably, examination of public datasets revealed high levels of IL8 transcripts in HER2-enriched as well as basal-like primary breast tumors, two subtypes characterized by a particularly poor prognosis. Moreover, IL8 expression correlated with high tumor grade and ER-negative status. Importantly, treatment with IL8-neutralizing antibodies prevented invasion of MCF10A-HER2/HER3 and BT474 cells in 3D cultures, highlighting the importance of IL8 autocrine signaling upon HER2/HER3 activation. CONCLUSIONS: Our findings demonstrate that HER2 and HER3 co-expression induces IL8 autocrine signaling, leading to the invasion of mammary cells. Agents targeting IL8 or its receptor CXCR1 may be useful for the treatment of HER2/HER3/IL8-positive breast cancers with invasive traits.