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Research Summary

Recent progress in cancer treatment has been made possible through new insights into the key genes and pathways that underlie most malignancies. Understanding how these central players trigger the early, stepwise progression of cancer will be essential to moving beyond incremental steps and toward revolutionary advances in cancer treatment and prevention. The Ellisen laboratory is broadly interested in identifying such genetic abnormalities, understanding how they influence the biology of cancer cells, and discovering how biology can inform the selection of the most effective therapy for each patient. We address these questions through basic research studies of key tumor-cell signaling pathways, and through molecular analysis of patient tumor samples conducted in partnership with collaborators in the fields of molecular diagnostics and computational biology. Our discoveries in the basic laboratory and through tumor analysis have already been translated to clinical trials that seek to identify new predictive markers, and new prevention and therapeutic strategies for breast and other cancers.

Research Projects

Our group has a broadly interest in how genetic abnormalities in breast cancer and related malignancies influence tumor biology, and how that biology can, in turn, be exploited to therapeutic advantage. We address these questions through basic research studies of key cancer drivers including DNA repair defects through BRCA1/2 and related pathways, and transcriptional reprogramming through the p53 gene family. Supporting and complementing these studies are sophisticated analyses of patient-derived precancerous and cancerous tissues. Recent innovative tissue-based studies have led to our discovery of novel cancer drivers, and have provided a unique window on early cancer pathogenesis, intratumoral heterogeneity and tumor progression. Our discoveries in the basic laboratory and through human tumor analysis are being applied in ongoing clinical trials that seek to identify predictive markers of response to specific therapeutics for breast and other cancers. Our ability to work at the interface of basic tumor biology and therapeutic application is strongly supported by our network of collaborators and by the research and clinical infrastructure of the Mass General Cancer Center.

The p53 family network in cancer biology and therapy

The p53 tumor suppressor is inactivated in more than 50% of sporadic human cancers, and heterozygous germline p53 mutations confers striking tumor predisposition. As a transcription factor and key nodal point for integrating cellular responses to DNA damage, p53 controls diverse cellular processes including cell cycle progression, apoptosis and angiogenesis. Through analysis of two p53-related genes, p63 and p73, we and others have defined a functional network through which these factors interact in human tumorigenesis. We have further defined a tissue-specific role for p63 as the enforcer of an epigenetically-controlled stem/progenitor state. Tumor-selective deregulation of p63 and its associated chromatin remodeling factors reprograms the transcriptome and thereby promotes proliferation, inhibits differentiation, and contributes to immune evasion. These findings likely explain the observation that p63 is over-expressed in a large variety of epithelial tumors, particularly squamous cell and breast carcinomas. Collectively, this work serves as a paradigm for analysis of transcriptional reprogramming in cancer, while potentially providing new therapeutic possibilities for multiple treatment-refractory malignancies.

BRCA1/2, hereditary cancer predisposition and prevention

Germline mutations in the DNA repair genes BRCA1 and BRCA2 confer dramatically elevated risk of cancers of the breast, ovary, and pancreas, yet the precise pathogenesis of BRCA1/2-associated cancer remains to be elucidated. Together with an international team of collaborators we are carrying out systematic studies of early events that give rise to these cancers, in part through detailed molecular analysis of normal and pre-cancerous tissues from BRCA1/2 mutation carriers. Defining the altered signaling and early cooperating events in this context is likely to reveal new markers of breast cancer predisposition and new targets for prevention. For example, our recently published single-cell genome analysis has revealed extensive chromosomal damage in BRCA1/2-mutant breast tissues that precedes any histological abnormalities. This seminal finding implies the existence of early cellular defects and associated vulnerabilities that could be exploited for cancer prevention in this setting.

Novel drivers of aggressive breast cancer subtypes

Our recent work employing advanced tumor molecular diagnostics has revealed gene fusions as novel drivers of an aggressive breast cancer subset. In a distinct aggressive breast cancer, triple-negative breast cancer (TNBC), extensive intratumoral heterogeneity is itself a driver that we have characterized through single-cell genomic and transcriptomic analysis. Our longstanding work on the biology of TNBC is supported by the institution-wide Triple-Negative Breast Cancer Program, which integrates basic research, translational and clinical studies together with human tumor propagation and high-throughput drug screening, all focused on overcoming drug resistance and improving outcomes for patients with TNBC.

Research Positions

Postdoctoral Research Fellow (1)

One Postdoctoral Research Fellow position is currently available. The candidate must have recently received a PhD degree in the biological sciences, and be highly motivated and well versed in basic molecular biology and biochemical techniques. The Fellow will have simultaneous academic appointments at the Massachusetts General Hospital and Harvard Medical School. The position provides a rich intellectual environment with full integration into the large research communities of the Mass General and Harvard. The laboratory studies fundamental mechanisms of tumorigenesis and their associated therapeutic implications in breast and other cancers. Topics of major interest include the p53 family of transcription factors, hereditary breast cancer and molecular genetics. We have identified fundamental mechanisms of the p53 family members in tumorigenesis (Cancer Cell 2017; 31:35) and normal development (Dev Cell 2014; 30:151), and have discovered novel genetic breast cancer drivers (Cancer Discovery 2017). We recently uncovered a new stress-induced tumor suppressor pathway involving regulation of mTOR activity (Nat Comm 2015; 6:7014), and revealed for the first time frequent gene regulatory mutations in breast cancer (Nature 2017; 547:55). Our ability to work at the interface of basic tumor biology, genetics and therapeutic application is strongly supported by the research and clinical infrastructure of the MGH Cancer Center.

To apply, please email a brief cover letter and CV to:

Leif W. Ellisen, MD, PhD
MGH Cancer Center
CPZN 4204
185 Cambridge Street
Boston, MA 02114


View a list of publications by researchers at the Ellisen Laboratory

Selected Publications

Qiao S, Koh SB, Vivekanandan V, Salunke D, Patra KC, Zaganjor E, Ross K, Mizukami Y, Jeanfavre S, Chen A, Mino-Kenudson M, Ramaswamy S, Clish C, Haigis M, Bardeesy N, and Ellisen LW. REDD1 loss reprograms lipid metabolism to drive progression of RAS-mutant tumors. Genes Dev. 2020 Jun 1;34(11-12):751-766.

Karaayvaz M, Silberman RE, Langenbucher A, Saladi SV, Ross KN, Zarcaro E, Desmond A, Yildirim M, Vivekanandan V, Ravichandran H, Mylavagnanam R, Specht MC, Ramaswamy S, Lawrence M, Amon A, Ellisen LW. Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers. Science Advances 2020;6:5.

Karaayvaz M, Cristea S, Gillespie SM, Patel AP, Mylvaganam R, Luo CC, Specht MC, Bernstein BE, Michor F, and Ellisen LW. Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq. Nature Communications. 2018 (In Press).

Matissek KJ, Onozato ML, Sun S, Zheng Z, Schultz A, Lee J, Patel K, Jerevall PL, Saladi SV, MacLeay A, Tavallai M, Badovinac-Crnjevic T, Barrios C, Be?e N, Chan A, Chavarri-Guerra Y, Debiasi M, Demirdogen E, Egeli U, Gökgöz S, Gomez H, Liedke P, Tasdelen I, Tolunay S, Werutsky G, St Louis J, Horick N, Finkelstein DM, Le LP, Bardia A, Goss PE, Sgroi DC, Iafrate AJ, Ellisen LW. Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor Positive Breast Cancer. Cancer Discovery2018 8(3):336-353.

Saladi, SV, Ross K, Karaayvaz M, Tata PR, Mou H, Rajagopal J, Ramaswamy S, and Ellisen LW. ACTL6A is co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation, Regenerative Proliferation and Poor Prognosis. Cancer Cell 2017 31:35-49.

Forster N, Saladi SV, Van Bragt M, Sfondouris ME, Jones FE, Li Z, and Ellisen LW. Basal cell signaling by p63 controls luminal progenitor function and lactation via NRG1. Developmental Cell 2014; 28:147-60.

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Group Members

  • James Thomas Coates, PhD
  • Mihriban Karaayvaz, PhD
  • Siang Boon Koh, PhD
  • Nsan Melkonjan
  • Aden Johnson-Shoucair
  • Nicole Smith, MS
  • Sheng Sun, PhD
  • Nayana Thimmiah, BS
  • Shufeng Zhou, PhD