Massachusetts General Hospital (MGH) researchers have identified for the first time how a highly aggressive form of breast cancer can evade one of the most powerful and effective drugs used to treat it.
185 Cambridge St
Boston, MA 02114
Leif Ellisen, MD, PhD
Center for Breast Cancer, Massachusetts General Hospital Cancer Center
Professor of Medicine
Harvard Medical School
- Center for Cancer Research
- Hematology & Medical Oncology
- Translational Research Laboratory
- Center for Cancer Risk Assessment
Explore the Ellisen Lab
Our laboratory specializes in work at the interface between basic tumor biology and therapeutic application. Understanding how key genes and pathways 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 that 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.
Our group has a broad 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 therapeutic resistance. 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.
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 triple-negative breast cancer (TNBC), extensive intratumoral heterogeneity is itself a driver that we have characterized through single-cell genomic and transcriptomic analysis, leading to our discovery of unanticipated drug resistance mechanisms with immediate therapeutic implications. Our longstanding work on the biology of TNBC is supported by the institutionwide 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.
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 precancerous 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 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.
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 mutation 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.
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
185 Cambridge Street
Boston, MA 02114
Coates JT, Sun S, Leshchiner I, Thimmiah N, Martin EE, McLoughlin D, Danysh BP, Slowik K, Jacobs RA, Rhrissorrakrai K, Utro F, Levovitz C, Denault E, Walmsley CS, Kambadakone A, Stone JR, Isakoff SJ, Parida L, Juric D, Getz G, Bardia A, and Ellisen LW. Parallel genomic alterations of antigen and payload targets mediate polyclonal acquired clinical resistance to sacituzumab govitecan in triple-negative breast cancer. Cancer Discovery. 2021 11:1-10.
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.
TROP2 is a cell-surface protein selectively expressed on tumor cells and targeted by emerging therapeutics including the antibody-drug conjugate sacituzumab govitecan (SG). Immunofluorescence (bottom) for TROP2 (red) in TNBC cells shows that the novel resistance mutation T256R results in TROP2 cytoplasmic mislocalization, which prevents SG binding.
Learn more about the people working in our lab.
- Program Director, Breast Medical Oncology
- Professor of Medicine, Harvard Medical School
- Clinical Director, Breast and Ovarian Cancer Genetics
- James T. Coates, PhD
- Mark W. Gonzalez Perez, BA
- Taisha Joseph, BS
- Siang Boon Koh, PhD
- Sarah Mueller, MD, PhD
- Malalage Nicole Peiris, PhD
- Zuen Ren, PhD
- Ilze Smidt, BS
- Nicole Smith, MS
- Sheng Sun, PhD
- Win Thant, BS
- Nayana Thimmiah, BS
- Bogang Wu, PhD