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Center for Cancer Research
Read the Ellisen Lab 2017-2018 Annual Report
Leif Ellisen, MD, PhDProgram DirectorCenter for Breast Cancer, Massachusetts General Hospital Cancer Center
Professor of MedicineHarvard Medical School
Cancer therapy is being revolutionized through the development of more selective and less toxic treatment approaches. A key to these advances is the identification of genetic abnormalities within tumor cells that are not present in normal tissues. The Ellisen laboratory is broadly interested in identifying these genetic abnormalities and understanding how they inﬂuence the biology of cancer cells and their microenviroment. We seek in turn to understand 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 and immune 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 led to clinical trials that seek to identify new predictive markers and new therapeutic strategies for breast and other cancers.
Leif W. Ellisen, MD, PhDPrincipal Investigator
Our group is broadly interested in how genetic abnormalities of breast and related cancers inﬂuence tumor biology, and how that biology can be exploited to therapeutic advantage. We address these questions through basic research studies of cancer genetics, molecular evolution and the resulting deregulation of key tumor cell signaling pathways. This work is complemented by molecular analyses of patient tissue samples conducted in partnership with collaborators in the fields of molecular diagnostics and computational biology. Our discoveries in the basic laboratory and through human tumor analysis are being applied in ongoing clinical trials that seek to identify new targets and predictive markers of therapy of 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 network in cancer biology and therapy
The p53 tumor suppressor is inactivated in more than 50% of sporadic human cancers, and patients carrying heterozygous germline p53 mutations show striking tumor predisposition. As a transcription factor andkey nodal point for integrating cellular responses to DNA damage, p53 regulates genes involved in 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 progenitor state. These findings are likely to explain the observation that p63 is over-expressed in a broad variety of epithelial tumors, particularly squamous cell and breast carcinomas. Our success in defining such novel functional interactions and contributions for the p53 family provides new therapeutic possibilities for multiple treatment-refractory malignancies.
P53 and TOR-associated metabolic reprogramming in tumorigenesis
Our efforts to identify new pathways regulated by p53 family members have yielded surprising insights into the re-wiring of cellular metabolism that drives carcinogenesis. A central player in this effect is REDD1, a p53-regulated gene we identified that functions as a critical regulator of redox status and the mechanistic Target of Rapamycin (mTOR) kinase. Most human tumors exhibit abnormalities of p53 and/or mTOR signaling, and our recent studies have demonstrated the contribution of REDD1to autophagy and metabolic homeostasis during tumorigenesis. We are currently using animal models, in vitro studies, and biochemical approaches to understand key metabolic dependencies of tumors that can be exploited to therapeutic advantage.
BRCA1/2, hereditary cancer predisposition and triple-negative breast cancer
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. We have launched a systematic study 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. This work is complemented by our detailed studies of triple-negative breast cancer (TNBC), an aggressive subtype that comprises 80% of tumors in BRCA1 mutation carriers. Our newly-launched Triple-Negative Breast Cancer Program 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.
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.
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 Email: firstname.lastname@example.org
View a list of publications by researchers at the Ellisen Laboratory
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, Beşe 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 Discovery 2018 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.
Qiao S, Dennis M, Song X, Vadysirisack DD, Salunke D, Nash Z, Yang Z, Liesa M, Yoshioka J, Matsuzawa S, Shirihai OS, Lee RT, Reed JC, Ellisen LW. A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity. Nature Communications. 2015; 6:7014-22.
Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag K, Rugo H, Liu MC, Stearns V, Come SE, Timms K, Hartman A-R, Borger DR, Finkelstein DM, Garber JE, Ryan PE , Winer EP, Goss PE, Ellisen LW. TBCRC009: A multi-center Phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J Clin Oncol 2015 33:1902-9.
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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