Photo of Leif W. Ellisen,  MD, PhD

Leif W. Ellisen, MD, PhD

Massachusetts General Hospital

Massachusetts General Hospital

Leif W. Ellisen, MD, PhD

Massachusetts General Hospital


  • Professor, Medicine, Harvard Medical School
  • Associate Physician, MGH Cancer Center, Massachusetts General Hospital



  • Member, Center Scientific Council

Research Abstract

Our group is broadly interested in how genetic abnormalities within cancer cells influence their biology, and how that biology can in turn be exploited to therapeutic advantage. We address these questions through basic research studies of key tumor cell signaling pathways, complemented by genetic analysis of patient tumor samples conducted through our companion laboratory, the MGH Translational Research Laboratory (TRL). 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 MGH Cancer Center.

The p53 Network in Cancer Biology and Therapy

The p53 tumor suppressor functions as a key nodal point for integrating cellular responses to DNA damage. As such, p53 regulates genes involved in diverse cellular processes including cell cycle progression, apoptosis, and angiogenesis. Our recent work has defined roles for the p53-related transcription factors p63 and p73 in breast, ovarian, and squamous cancers, including the refractory “triple-negative” breast cancer subtype which occurs commonly in BRCA1 mutation carriers. Our success in defining novel functional interactions within the p53 family provides new therapeutic possibilities for these treatment-refractory malignancies.

TOR Signaling and the p53-Regulated Stress Response

One gene to emerge from our efforts to identify new pathways regulated by p53 family members is REDD1, a critical negative regulator of the TOR kinase that modulates the activity of the Tuberous Sclerosis tumor suppressor complex. Most human tumors exhibit abnormalities of p53 and/or TOR signaling, and indeed our biochemical and in vivo studies have demonstrated that REDD1 itself functions in a novel tumor suppressor pathway. We are currently using animal models, in vitro studies and biochemical approaches to understand the mechanisms of REDD1-mediated tumor suppression.

Tumor Genotyping to Drive Personalized Cancer Therapy

Activation of diverse oncogenes (e.g. RAS, RAF, EGFR) through somatic mutation not only causes cancer, but is now known to be an important determinant of the clinical response to targeted therapeutics. Until recently, identifying such abnormalities was restricted to research settings, as the technologies required for routine, high-performance tumor genotyping were not available. At the MGH TRL we have developed and validated high-throughput clinical diagnostic platforms for broad-based tumor genetic analysis. The availability of tumor genotyping for our large cancer patient population is accelerating the clinical trials process and is providing remarkable new opportunities for translational research.



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  • Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag KJ, Rugo HS, Liu MC, Stearns V, Come SE, Timms KM, Hartman AR, Borger DR, Finkelstein DM, Garber JE, Ryan PD, Winer EP, Goss PE, Ellisen LW. TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer. J Clin Oncol 2015. PubMed
  • 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. Nat Commun 2015; 6:7014. PubMed
  • Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 2014. PubMed
  • Zhao R, Fallon TR, Saladi SV, Pardo-Saganta A, Villoria J, Mou H, Vinarsky V, Gonzalez-Celeiro M, Nunna N, Hariri LP, Camargo F, Ellisen LW, Rajagopal J. Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells. Dev Cell 2014; 30:151-65. PubMed
  • Wakimoto H, Tanaka S, Curry WT, Loebel F, Zhao D, Tateishi K, Chen J, Klofas LK, Lelic N, Kim JC, Dias-Santagata D, Ellisen LW, Borger DR, Fendt SM, Vander Heiden MG, Batchelor TT, Iafrate AJ, Cahill DP, Chi AS. Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas. Clin Cancer Res 2014. PubMed
  • Dienstmann R, Dong F, Borger D, Dias-Santagata D, Ellisen LW, Le LP, Iafrate AJ. Standardized decision support in next generation sequencing reports of somatic cancer variants. Mol Oncol 2014. PubMed
  • Borger DR, Goyal L, Yau T, Poon RT, Ancukiewicz M, Deshpande V, Christiani DC, Liebman HM, Yang H, Kim H, Yen K, Faris JE, Iafrate AJ, Kwak EL, Clark JW, Allen JN, Blaszkowsky LS, Murphy JE, Saha SK, Hong TS, Wo JY, Ferrone CR, Tanabe KK, Bardeesy N, Straley KS, Agresta S, Schenkein DP, Ellisen LW, Ryan DP, Zhu AX. Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma. Clin Cancer Res 2014; 20:1884-90. PubMed
  • Russo AL, Borger DR, Szymonifka J, Ryan DP, Wo JY, Blaszkowsky LS, Kwak EL, Allen JN, Wadlow RC, Zhu AX, Murphy JE, Faris JE, Dias-Santagata D, Haigis KM, Ellisen LW, Iafrate AJ, Hong TS. Mutational analysis and clinical correlation of metastatic colorectal cancer. Cancer 2014. PubMed
  • Forster N, Saladi SV, van Bragt M, Sfondouris ME, Jones FE, Li Z, Ellisen LW. Basal cell signaling by p63 controls luminal progenitor function and lactation via NRG1. Dev Cell 2014; 28:147-60. PubMed
  • Akhavanfard S, Vargas SO, Han M, Nitta M, Chang CB, Le LP, Fazlollahi L, Nguyen Q, Ma Y, Cosper A, Dias-Santagata D, Han JY, Bergethon K, Borger DR, Ellisen LW, Pomeroy SL, Haber DA, Iafrate AJ, Rivera MN. Inactivation of the tumor suppressor WTX in a subset of pediatric tumors. Genes Chromosomes Cancer 2013; 53:67-77. PubMed
  • Ramsey MR, 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. PubMed
  • McBride SM, Rothenberg SM, Faquin WC, Chan AW, Clark JR, Ellisen LW, Wirth LJ. Mutation frequency in 15 common cancer genes in high-risk head and neck squamous cell carcinoma. Head Neck 2014. PubMed
  • Chabner BA, Ellisen LW, Iafrate AJ. Personalized medicine: hype or reality. Oncologist 2013; 18:640-3. PubMed
  • Chi AS, Batchelor TT, Yang D, Dias-Santagata D, Borger DR, Ellisen LW, Iafrate AJ, Louis DN. BRAF V600E mutation identifies a subset of low-grade diffusely infiltrating gliomas in adults. J Clin Oncol 2013; 31:e233-6. PubMed
  • He L, Torres-Lockhart K, Forster N, Ramakrishnan S, Greninger P, Garnett MJ, McDermott U, Rothenberg SM, Benes CH, Ellisen LW. Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma. 2013; 3:324-37. PubMed
  • Patenaude AF, Tung N, Ryan PD, Ellisen LW, Hewitt L, Schneider KA, Tercyak KP, Aldridge J, Garber JE. Young adult daughters of BRCA1/2 positive mothers: What do they know about hereditary cancer and how much do they worry? 2013. PubMed
  • Ibrahim YH, García-García C, Serra V, He L, Torres-Lockhart K, Prat A, Anton P, Cozar P, Guzmán M, Grueso J, Rodríguez O, Calvo MT, Aura C, Díez O, Rubio IT, Pérez J, Rodón J, Cortés J, Ellisen LW, Scaltriti M, Baselga J. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. 2012; 2:1036-47. PubMed
  • Gallant-Behm CL, Ramsey MR, Bensard CL, Nojek I, Tran J, Liu M, Ellisen LW, Espinosa JM. {Delta}Np63留 represses anti-proliferative genes via H2A.Z deposition. Genes Dev 2012; 26:2325-36. PubMed
  • Chi AS, Batchelor TT, Dias-Santagata D, Borger D, Stiles CD, Wang DL, Curry WT, Wen PY, Ligon KL, Ellisen L, Louis DN, Iafrate AJ. Prospective, high-throughput molecular profiling of human gliomas. J. Neurooncol. 2012; 110:89-98. PubMed
  • Rothenberg SM, Ellisen LW. The molecular pathogenesis of head and neck squamous cell carcinoma. J Clin Invest 2012; 122:1951-7. PubMed
  • Ramsey MR, He L, Forster N, Ory B, Ellisen LW. Physical association of HDAC1 and HDAC2 with p63 mediates transcriptional repression and tumor maintenance in squamous cell carcinoma. Cancer Res 2011; 71:4373-9. PubMed
  • Ellisen LW. PARP inhibitors in cancer therapy: promise, progress, and puzzles. Cancer Cell 2011; 19:165-7. PubMed
  • Ory B, Ramsey MR, Wilson C, Vadysirisack DD, Forster N, Rocco JW, Rothenberg SM, Ellisen LW. A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma. J Clin Invest 2011; 121:809-20. PubMed
  • Yang C, Hayashida T, Forster N, Li C, Shen D, Maheswaran S, Chen L, Anderson KS, Ellisen LW, Sgroi D, Schmidt EV. The integrin alpha(v)beta(3-5) ligand MFG-E8 is a p63/p73 target gene in triple-negative breast cancers but exhibits suppressive functions in ER(+) and erbB2(+) breast cancers. Cancer Res 2011; 71:937-45. PubMed
  • Ibrahim N, He L, Leong CO, Xing D, Karlan BY, Swisher EM, Rueda BR, Orsulic S, Ellisen LW. BRCA1-associated epigenetic regulation of p73 mediates an effector pathway for chemosensitivity in ovarian carcinoma. Cancer Res 2010; 70:7155-65. PubMed
  • Ellisen LW. Smoking and emphysema: the stress connection. Nat Med 2010; 16:754-5. PubMed
  • Dias-Santagata D, Akhavanfard S, David SS, Vernovsky K, Kuhlmann G, Boisvert SL, Stubbs H, McDermott U, Settleman J, Kwak EL, Clark JW, Isakoff SJ, Sequist LV, Engelman JA, Lynch TJ, Haber DA, Louis DN, Ellisen LW, Borger DR, Iafrate AJ. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol Med 2010; 2:146-58. PubMed
  • Horak P, Crawford AR, Vadysirisack DD, Nash ZM, DeYoung MP, Sgroi D, Ellisen LW. Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis. Proc Natl Acad Sci U S A 2010; 107:4675-80. PubMed
  • Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, Juul N, Leong CO, Calogrias D, Buraimoh A, Fatima A, Gelman RS, Ryan PD, Tung NM, De Nicolo A, Ganesan S, Miron A, Colin C, Sgroi DC, Ellisen LW, Winer EP, Garber JE. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol 2010; 28:1145-53. PubMed
  • Zhong L, D'Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T, Clish CB, Vaitheesvaran B, Iliopoulos O, Kurland I, Dor Y, Weissleder R, Shirihai OS, Ellisen LW, Espinosa JM, Mostoslavsky R. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 2010; 140:280-93. PubMed
  • Michaud WA,Nichols AC,Mroz EA,Faquin WC,Clark JR,Begum S,Westra WH,Wada H,Busse PM,Ellisen LW,Rocco JW. Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma. Clin Cancer Res 2009; 15:1645-54. PubMed
  • Li N, Singh S, Cherukuri P, Li H, Yuan Z, Ellisen LW, Wang B, Robbins D, Direnzo J. Reciprocal Intra-Epithelial Interactions between TP63 and Hedgehog Signaling Regulate Quiescence and Activation of Progenitor Elaboration by Mammary Stem Cells. Stem Cells 2008; 26:1253-64. PubMed
  • Harvey KF, Mattila J, Sofer A, Bennett FC, Ramsey MR, Ellisen LW, Puig O, Hariharan IK. FOXO-regulated transcription restricts overgrowth of Tsc mutant organs. J Cell Biol 2008; 180:691-6. PubMed
  • DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 2008; 22:239-51. PubMed
  • Deyoung MP, Ellisen LW. p63 and p73 in human cancer: defining the network. Oncogene 2007; 26:5169-83. PubMed
  • Leong CO, Vidnovic N, Deyoung MP, Sgroi D, Ellisen LW. The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. J Clin Invest 2007; 117:1370-80. PubMed
  • Wang H, Kubica N, Ellisen LW, Jefferson LS, Kimball SR. Dexamethasone represses signaling through the mammalian target of rapamycin in muscle cells by enhancing expression of REDD1. J Biol Chem 2006; 281:39128-34. PubMed
  • Deyoung MP, Johannessen CM, Leong CO, Faquin W, Rocco JW, Ellisen LW. Tumor-Specific p73 Up-regulation Mediates p63 Dependence in Squamous Cell Carcinoma. Cancer Res 2006; 66:9362-8. PubMed
  • Carroll DK, Carroll JS, Leong CO, Cheng F, Brown M, Mills AA, Brugge JS, Ellisen LW. p63 regulates an adhesion programme and cell survival in epithelial cells. Nat Cell Biol 2006; 8:551-61. PubMed
  • Rocco JW, Leong CO, Kuperwasser N, DeYoung MP, Ellisen LW. p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. Cancer Cell 2006; 9:45-56. PubMed
  • Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18:2893-904. PubMed