Community Action Needed: Please respond to the NIH RFI
ZFIN ID: ZDB-LAB-191118-1
Nissim Lab
PI/Director: Nissim, Sahar
Contact Person: Nissim, Sahar
Email: snissim@bwh.harvard.edu
URL: http://Nissimlab.org
Address: Brigham and Women’s Hospital, Genetics Division New Research Building room 458 77 Ave Louis Pasteur Boston, MA 02115
Country: United States
Phone: 617-525-4743
Fax:
Line Designation: bw


GENOMIC FEATURES ORIGINATING FROM THIS LAB
Show all 2 genomic features


STATEMENT OF RESEARCH INTERESTS
Pancreatic cancer is one of the most deadly cancers, with notoriously ineffective treatment options. Our research group leverages developmental biology, genetic discovery in hereditary pancreatic cancer families, transcriptomic and proteomic approaches, and pre-clinical studies in zebrafish and mouse models to characterize novel determinants of cancer initiation and develop strategies for prevention and treatment of pancreatic cancer.

In about 10% of cases, pancreatic cancer occurs as multiple cases in a single family, raising suspicion of a hereditary cause. The explanation for most of these families has not been identified. Finding and understanding the genetic basis of “unsolved” pancreatic cancer families can help identify who is at risk and should have surveillance in the family. More broadly, understanding how a single inherited mutation leads to pancreatic cancer can gives us precious clues into why the cancer happens and new strategies for treatment and prevention. To address this need, the Nissim Lab has developed a research pipeline for discovery, validation, and characterization of new genetic causes of hereditary pancreatic cancer. By whole genome sequencing analysis, we can identify inherited mutations associated with pancreatic cancer in multiple family relatives. To validate the causality of these mutations in cancer, we assess how these mutations impact cancer risk in zebrafish populations. To characterize these novel cancer pathways, we interrogate function in the context of zebrafish pancreas development in conjunction with unbiased transcriptomic and proteomic approaches. As a proof-of-principle, we recently identified the cause of pancreatic cancer in a previously-unsolved family with 5 cases, validated the causality of this mutation in zebrafish populations, and discovered that the mutation alters the intracellular trafficking of KRAS (Nissim et al., Nature Genetics, 2019). We are now exploring the therapeutic potential of targeting this pathway in pancreatic cancer.

Sitting at this intersection of longitudinal care of hereditary pancreatic cancer families in the clinic, genome analysis, and zebrafish cancer models at the lab bench, our research group is well-positioned to continue making pivotal discoveries that will advance our understanding and management of pancreatic cancer.


LAB MEMBERS


ZEBRAFISH PUBLICATIONS OF LAB MEMBERS
Nissim, S., Leshchiner, I., Mancias, J.D., Greenblatt, M.B., Maertens, O., Cassa, C.A., Rosenfeld, J.A., Cox, A.G., Hedgepeth, J., Wucherpfennig, J.I., Kim, A.J., Henderson, J.E., Gonyo, P., Brandt, A., Lorimer, E., Unger, B., Prokop, J.W., Heidel, J.R., Wang, X.X., Ukaegbu, C.I., Jennings, B.C., Paulo, J.A., Gableske, S., Fierke, C.A., Getz, G., Sunyaev, S.R., Wade Harper, J., Cichowski, K., Kimmelman, A.C., Houvras, Y., Syngal, S., Williams, C., Goessling, W. (2019) Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer. Nature Genetics. 51(9):1308-1314
Nissim, S., Weeksb, O., Talbot, J.C., Hedgepeth, J.W., Wucherpfennig, J., Schatzman-Bone, S., Swinburne, I., Cortes, M., Alexa, K., Megason, S., North, T.E., Amacher, S.L., Goessling, W. (2016) Iterative use of nuclear receptor Nr5a2 regulates multiple stages of liver and pancreas development. Developmental Biology. 418(1):108-23
Cox, A.G., Tsomides, A., Kim, A.J., Saunders, D., Hwang, K.L., Evason, K.J., Heidel, J., Brown, K.K., Yuan, M., Lien, E.C., Lee, B.C., Nissim, S., Dickinson, B., Chhangawala, S., Chang, C.J., Asara, J.M., Houvras, Y., Gladyshev, V.N., Goessling, W. (2016) Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America. 113(38):E5562-71
Cox, A.G., Hwang, K.L., Brown, K.K., Evason, K.J., Beltz, S., Tsomides, A., O'Connor, K., Galli, G.G., Yimlamai, D., Chhangawala, S., Yuan, M., Lien, E.C., Wucherpfennig, J., Nissim, S., Minami, A., Cohen, D.E., Camargo, F.D., Asara, J.M., Houvras, Y., Stainier, D.Y., Goessling, W. (2016) Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nature cell biology. 18(8):886-96
Mancias, J.D., Pontano Vaites, L., Nissim, S., Biancur, D.E., Kim, A.J., Wang, X., Liu, Y., Goessling, W., Kimmelman, A.C., Harper, J.W. (2015) Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. eLIFE. 4
Esain, V., Kwan, W., Carroll, K.J., Cortes, M., Liu, S.Y., Frechette, G.M., Sheward, L.M., Nissim, S., Goessling, W., North, T.E. (2015) Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via PGE2 and P-selectin Activity. Stem Cells. 33(8):2596-612
Carroll, K.J., Esain, V., Garnaas, M.K., Cortes, M., Dovey, M.C., Nissim, S., Frechette, G.M., Liu, S.Y., Kwan, W., Cutting, C.C., Harris, J.M., Gorelick, D.A., Halpern, M.E., Lawson, N.D., Goessling, W., North, T.E. (2014) Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche. Developmental Cell. 29:437-53
Nissim, S., Sherwood, R.I., Wucherpfennig, J., Saunders, D., Harris, J.M., Esain, V., Carroll, K.J., Frechette, G.M., Kim, A.J., Hwang, K.L., Cutting, C.C., Elledge, S., North, T.E., and Goessling, W. (2014) Prostaglandin E2 regulates liver versus pancreas cell-fate decisions and endodermal outgrowth. Developmental Cell. 28(4):423-437