Sahar Nissim, MD, PhD

Investigator, Hale Family Research Center

Division Of Genetics, Brigham And Women’s Hospital

Division Of Gastroenterology, Brigham And Women’s Hospital

Division Of Genetics And Prevention,                                   Dana-Farber Cancer Institute

Assistant Professor Of Medicine, Harvard Medical School 

Harvard-MIT Program In Health Sciences And Technology

 

Bio     Research Interests     Key Publications    Nissim Lab Website

Bio

Dr. Sahar Nissim, MD, PhD is a cancer geneticist at the Dana-Farber Cancer Institute and a gastroenterologist at Brigham And Women’s Hospital. He is a practicing clinician at the Dana-Farber Cancer Institute Center For Cancer Genetics And Prevention where he specializes in the care of individuals with a strong family history of pancreatic cancer. He also runs an independent laboratory focused on discovery and characterization of germline determinants of pancreatic cancer.

Dr. Nissim’s work reflects an intersection of PhD training in genetics and developmental biology at Harvard Medical School with Dr. Cliff Tabin, post-doctoral training in innovative zebrafish cancer models with Dr. Wolfram Goessling, and clinical training in internal medicine and gastroenterology at Brigham And Women’s Hospital and hereditary cancer syndromes at the Dana-Farber Cancer Institute. Dr. Nissim joined the faculty of Harvard Medical School and Dana-Farber Cancer Institute in 2019.

Research Interests

The Nissim Lab seeks to discover and characterize germline determinants of pancreatic cancer in order to pioneer new interception and treatment strategies. Towards this goal, our research program leverages experience in high-throughput zebrafish population studies, pancreas organ development and inflammation, transgenic mouse models, unbiased transcriptomic and proteomic analyses, and gene discovery in patient families.

Germline determinants of pancreatic cancer span from common risk variants implicated by Genome-Wide Association Studies (GWAS) to rare high-effect etiologies that explain familial clustering of pancreatic cancer.

One major focus in the lab is to understand the mechanisms by which GWAS loci modify risk of pancreatic cancer, and to determine whether pharmacologically targeting these pathways can actively prevent pancreatic cancer formation in high-risk individuals.

A second major focus is to uncover the heritable basis for family clusters of pancreatic cancer. About 10% of pancreatic cancer cases are thought to be associated with a rare inherited genetic mutation, and while causative genes such as BRCA2 have been identified in some of these families, the vast majority of these families remain “unsolved”. Germline mutations with large effect on PDAC risk are relatively under-studied compared to somatic mutations, yet can provide precious clues to cancer formation, new prognostic and diagnostic markers, and critically-needed alternative strategies for treatment. In one family encountered in the clinic with five cases of pancreatic cancer, we recently identified a mutation in a gene RABL3 never before associated with cancer risk. By recapitulating this mutation in large zebrafish population studies, we validated its role in promoting cancer. We further discovered that the mutation alters a key step in the intracellular trafficking of KRAS, one of the most common drivers in cancer. We are now exploring the therapeutic potential of targeting this node in pancreatic cancer. Though rare, each hereditary pancreatic cancer family has the potential to uncover fundamental insights into cancer biology with broad translational implications.

Key Publications

Nissim S, Leshchiner I, Mancias JD, Greenblatt MB, Maertens O, Cassa CA, Rosenfeld JA, Cox AG, Hedgepeth J, Wucherpfennig JI, Kim AJ, Henderson JE, Gonyo P, Brandt A, Lorimer E, Unger B, Prokop JW, Heidel JR, Wang XX, Ukaegbu CI, Jennings BC, Paulo JA, Gableske S, Fierke CA, Getz G, Sunyaev SR, Wade Harper J, Cichowski K, Kimmelman AC, Houvras Y, Syngal S, Williams C, Goessling W. Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer. Nat Genet. 2019; 51(9):1308-14. PMID: 31406347.

Cox AG, Tsomides A, Kim AJ, Saunders D, Hwang KL, Evason KJ, Heidel J, Brown KK, Yuan M, Lien EC, Lee BC, Nissim S, Dickinson B, Chhangawala S, Chang CJ, Asara JM, Houvras Y, Gladyshev VN, Goessling W. Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis. Proc Natl Acad Sci U S A. 2016; 113(38):E5562-71. PMID: 27588899.

Nissim S*, Weeks O*, Talbot JC, Hedgepeth JW, Wucherpfennig J, Schatzman-Bone S, Swinburne I, Cortes M, Alexa K, Megason S, North TE, Amacher SL, Goessling W. Iterative use of nuclear receptor Nr5a2 regulates multiple stages of liver and pancreas development. Dev Biol. 2016; 418(1):108-23. PMID: 27474396.

Cox AG, Hwang KL, Brown KK, Evason K, Beltz S, Tsomides A, O’Connor K, Galli GG, Yimlamai D, Chhangawala S, Yuan M, Lien EC, Wucherpfennig J, Nissim S, Minami A, Cohen DE, Camargo FD, Asara JM, Houvras Y, Stainier DYR, Goessling W. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat Cell Biol. 2016; 18(8):886-96. PMID: 27428308.

Mancias JD, Pontano Vaites L, Nissim S, Biancur DE, Kim AJ, Wang X, Liu Y, Goessling W, Kimmelman AC, Harper JW. Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. Elife. 2015; 4. PMID: 26436293.

Nissim S, Sherwood RI, Wucherpfennig J, Saunders D, Harris JM, Esain V, Carroll KJ, Frechette GM, Kim AJ, Hwang KL, Cutting CC, Elledge S, North TE, Goessling W. Prostaglandin E2 regulates liver versus pancreas cell-fate decisions and endodermal outgrowth. Dev Cell. 2014; 28(4):423-37. PMID: 24530296.

Nissim S, Idos GE, Wu B. Genetic markers of malignant transformation in intraductal papillary mucinous neoplasm of the pancreas: a meta-analysis. Pancreas. 2012; 41(8):1195-205. PMID: 22750975.

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