Ellisen

Ellisen Lab

Research topics include: P53 and human tumorigenesis; breast cancer

Overview

Leif Ellisen, MD, PhD
Program Director
Center for Breast Cancer, Massachusetts General Hospital Cancer Center

Professor of Medicine
Harvard Medical School

Research Summary

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.

Read the Ellisen Lab's Annual Report in full 

 

Group Members

Leif W. Ellisen, MD, PhD
Principal Investigator

Group Members

  • Mihriban Karaayvaz, PhD
  • Siang Boon Koh, PhD
  • Karina Matissek, PhD
  • Aiko Nagayama, MD
  • Kristofer Patel, BA
  • Shuxi Qiao, PhD
  • Srinivas Vinod Saladi, PhD
  • Devika Salunke, MS
  • Sheng Sun, PhD

Research Projects

Our group is broadly interested in how genetic abnormalities within cancer cells influence their 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 tumor analysis are being applied in ongoing clinical trials that seek to identify new targets and predictive markers for 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.

Cancer genetics as a defining feature of biology and therapy

New technologies and more robust computational approaches are enabling the identification of major new cancer driver genetic events. Our recent work together with collaborators has revealed mutational signatures of specific failed DNA repair pathways, and additionally uncovered the first recurrent, breast cancer-specific gene regulatory mutations. We have also identified a host of new breast cancer drivers in the form of intergenic fusions, which are both relatively common and associated with aggressive tumor behavior and poor outcomes. Through complementary in vitro and in vivo studies we seek to understand the mechanisms of such driver events. Furthermore, we strive to develop novel diagnostic and prognostic approaches based on these findings, together with stratified clinical trials targeting these alterations using emerging therapeutics.

Developmental history, transcriptional landscapes and actionable epigenetic states

Recent elegant studies have revealed how the developmental history of cancers relates to the malignant cell state and the susceptibility of cells to particular driver genetic events. One window into these findings is our work on p63, a lineage-specific transcription factor of the p53 family that is over-expressed in a broad variety of epithelial tumors, particularly squamous cell and breast carcinomas. While our early work defined a functional network through which the p53 family of factors interact in tumorigenesis, our recent studies demonstrate how deregulation of p63 and its cofactors alters the epigenetic landscape in these cancers. The resulting stem/progenitor state explains the aggressiveness of p63-amplified tumors, but also elucidates critical interactions with the tumor microenvironment that can be manipulated to therapeutic advantage. Accordingly, our deep investigation of the transcriptional cofactor and epigenetic landscapes of these tumors is likely to yield high-impact advances.

BRCA1/2, early pathogenesis and the challenge of triple-negative breast cancer

Germline mutations in the DNA repair genes BRCA1 and BRCA2 confer dramatically elevated risk of cancers of the breast, ovary, pancreas and prostate, yet the precise pathogenesis of BRCA1/2-associated cancer remains to be elucidated. We have undertaken a systematic study of early events that give rise to these cancers as a model of early cancer pathogenesis. Work to date points to new mechanisms of early immune invasion, while defining early cooperating events in this context is likely to reveal both 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 TNBC Program integrates basic research, translational studies and clinical trials, together with ex-vivo 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.

Contact

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: lellisen@mgh.harvard.edu

 

Publications

View a list of publications by researchers at the Ellisen Laboratory

Selected Publications

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 Apr 28;6:7014.

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.

Ramsey M, Wilson C, Ory B, Rothenberg SM, Faquin W, Mills AA, Ellisen LW. FGFR2 Signaling Underlies p63 Oncogenic Function in Squamous Cell Carcinoma. J Clin Invest 2013; 123:3525-38.

He L, Torres-Lockhart K, Forster N, Ramkrishnan S, Greninger P, Garnett MJ, McDermott U, Rothenberg SM, Benes CH, and Ellisen LW. Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma. Cancer Discovery 2013; 3:324-37.

 

Contact

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Ellisen Laboratory

GRJ-90455 Fruit Street Boston, MA 02114

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