ZFIN ID: ZDB-PERS-040811-2
Leach, Steven D.
Email: stleach@jhmi.edu
Address: Professor of Surgery, Oncology and Cell Biology McKusick-Nathans Institute of Genetic Medicine Johns Hopkins University 733 N. Broadway / BRB 471 Baltimore, MD 21205 tel 410-955-5765 fax 410-502-1853 sleach1@jhmi.edu
Phone: 410-955-5765
Fax: 410-502-1853

Our laboratory studies studies pancreatic progenitor cells in developing, regenerating and neoplastic pancreas, using both mouse and zebrafish model systems. Work from our lab has significantly contributed to our current understanding of pancreatic progenitor cells in adult and embryonic pancreas. These contributions include the initial characterization of Nestin-expressing epithelial cells as lineage-restricted exocrine progenitors in developing mouse pancreas, the identification of Notch as a critical regulator of exocrine differentiation in developing mouse and zebrafish pancreas, the identification and localization of Notch-responsive progenitor cells in developing zebrafish pancreas, and the identification of a critical role for epithelial Hedgehog signaling in pancreatic regeneration. In addition, our group was the first to identify abnormal Notch pathway activation as a characteristic feature of human pancreatic cancer. Most recently, our group generated the first zebrafish model of pancreatic cancer, and also identified a novel dedicated centroacinar progenitor cell in adult mouse pancreas. These studies of pancreatic development and pancreatic epithelial plasticity have widened our view pancreatic progenitor biology, and demonstrated previously unexpected plasticity among adult pancreatic epithelial cell types. This work has obvious relevance for human pancreatic disease, including diabetes and pancreatic cancer.

Park, J.T., Leach, S.D. (2018) Zebrafish model of KRAS-initiated pancreatic cancer. Animal cells and systems. 22:353-359
Wang, Y.J., Park, J.T., Parsons, M.J., Leach, S.D. (2015) Fate mapping of ptf1a-expressing cells during pancreatic organogenesis and regeneration in zebrafish. Developmental Dynamics : an official publication of the American Association of Anatomists. 244(6):724-35
Park, J.T., Johnson, N., Liu, S., Levesque, M., Wang, Y.J., Ho, H., Huso, D., Maitra, A., Parsons, M.J., Prescott, J.D., Leach, S.D. (2015) Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey. Oncogene. 34(21):2801-6
Provost, E., Bailey, J.M., Aldrugh, S., Liu, S., Iacobuzio-Donahue, C., Leach, S.D. (2014) The Tumor Suppressor rpl36 Restrains KRAS(G12V)-Induced Pancreatic Cancer. Zebrafish. 11(6):551-9
Kelkar, D.S., Provost, E., Chaerkady, R., Muthusamy, B., Manda, S.S., Subbannayya, T., Selvan, L.D., Wang, C.H., Datta, K.K., Woo, S., Dwivedi, S.B., Renuse, S., Getnet, D., Huang, T.C., Kim, M.S., Pinto, S.M., Mitchell, C.J., Madugundu, A.K., Kumar, P., Sharma, J., Advani, J., Dey, G., Balakrishnan, L., Syed, N., Nanjappa, V., Subbannayya, Y., Goel, R., Prasad, T.S., Bafna, V., Sirdeshmukh, R., Gowda, H., Wang, C., Leach, S.D., Pandey, A. (2014) Annotation of the zebrafish genome through an integrated transcriptomic and proteomic analysis. Molecular & cellular proteomics : MCP. 13(11):3184-98
Schiavone, M., Rampazzo, E., Casari, A., Battilana, G., Persano, L., Moro, E., Liu, S., Leach, S.D., Tiso, N., Argenton, F. (2014) Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer. Disease models & mechanisms. 7(7):883-94
Park, J.T., and Leach, S.D. (2013) TAILOR: transgene activation and inactivation using lox and rox in zebrafish. PLoS One. 8(12):e85218
Matsuda, H., Parsons, M.J., and Leach, S.D. (2013) Aldh1-expressing endocrine progenitor cells regulate secondary islet formation in larval zebrafish pancreas. PLoS One. 8(9):e74350
Pashos, E., Tae Park, J., Leach, S., and Fisher, S. (2013) Distinct enhancers of ptf1a mediate specification and expansion of ventral pancreas in zebrafish. Developmental Biology. 381(2):471-81
Provost, E., Weier, C.A., and Leach, S.D. (2013) Multiple ribosomal proteins are expressed at high levels in developing zebrafish endoderm and are required for normal exocrine pancreas development. Zebrafish. 10(2):161-169
Provost, E., Wehner, K.A., Zhong, X., Ashar, F., Nguyen, E., Green, R., Parsons, M.J., and Leach, S.D. (2012) Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development. Development (Cambridge, England). 139(17):3232-3241
Yamazoe, S., Shestopalov, I.A., Provost, E., Leach, S.D., and Chen, J.K. (2012) Cyclic Caged Morpholinos: Conformationally Gated Probes of Embryonic Gene Function. Angewandte Chemie (International ed. in English). 51(28):6908-6911
Liu, S., and Leach, S.D. (2011) Zebrafish models for cancer. Annual review of pathology. 6:71-93
Liu, S., and Leach, S.D. (2011) Screening Pancreatic Oncogenes in Zebrafish Using the Gal4/UAS System. Methods in cell biology. 105:367-381
Kent, O.A., Chivukula, R.R., Mullendore, M., Wentzel, E.A., Feldmann, G., Lee, K.H., Liu, S., Leach, S.D., Maitra, A., and Mendell, J.T. (2010) Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway. Genes & Development. 24(24):2754-2759
Parsons, M.J., Pisharath, H., Yusuff, S., Moore, J.C., Siekmann, A.F., Lawson, N., and Leach, S.D. (2009) Notch-responsive cells initiate the secondary transition in larval zebrafish pancreas. Mechanisms of Development. 126(10):898-912
Hama, K., Provost, E., Baranowski, T.C., Rubinstein, A.L., Anderson, J.L., Leach, S.D., and Farber, S.A. (2009) In vivo imaging of zebrafish digestive organ function using multiple quenched fluorescent reporters. American journal of physiology. Gastrointestinal and liver physiology. 296(2):G445-G453
Park, S.W., Davison, J.M., Rhee, J., Hruban, R.H., Maitra, A., and Leach, S.D. (2008) Oncogenic KRAS Induces Progenitor Cell Expansion and Malignant Transformation in Zebrafish Exocrine Pancreas. Gastroenterology. 134(7):2080-2090
Dong, P.D., Provost, E., Leach, S.D., and Stainier, D.Y. (2008) Graded levels of Ptf1a differentially regulate endocrine and exocrine fates in the developing pancreas. Genes & Development. 22(11):1445-1450
Davison, J.M., Woo Park, S., Rhee, J.M., and Leach, S.D. (2008) Characterization of Kras-mediated pancreatic tumorigenesis in zebrafish. Methods in enzymology. 438:391-417
Halpern, M.E., Rhee, J., Goll, M.G., Akitake, C.M., Parsons, M., and Leach, S.D. (2008) Gal4/UAS transgenic tools and their application to zebrafish. Zebrafish. 5(2):97-110
Godinho, L., Williams, P.R., Claassen, Y., Provost, E., Leach, S.D., Kamermans, M., and Wong, R.O. (2007) Nonapical symmetric divisions underlie horizontal cell layer formation in the developing retina in vivo. Neuron. 56(4):597-603
Provost, E., Rhee, J., and Leach, S.D. (2007) Viral 2A peptides allow expression of multiple proteins from a single ORF in transgenic zebrafish embryos. Genesis (New York, N.Y. : 2000). 45(10):625-629
Davison, J.M., Akitake, C.M., Goll, M.G., Rhee, J.M., Gosse, N., Baier, H., Halpern, M.E., Leach, S.D., and Parsons, M.J. (2007) Transactivation from Gal4-VP16 transgenic insertions for tissue-specific cell labeling and ablation in zebrafish. Developmental Biology. 304(2):811-824
Pisharath, H., Rhee, J.M., Swanson, M.A., Leach, S.D., and Parsons, M.J. (2007) Targeted ablation of beta cells in the embryonic zebrafish pancreas using E. coli nitroreductase. Mechanisms of Development. 124(3):218-229
Godinho, L., Mumm, J.S., Williams, P.R., Schroeter, E.H., Koerber, A., Park, S.W., Leach, S.D., and Wong, R.O. (2005) Targeting of amacrine cell neurites to appropriate synaptic laminae in the developing zebrafish retina. Development (Cambridge, England). 132(22):5069-5079
Esni, F., Ghosh, B., Biankin, A.V., Lin, J.W., Albert, M.A., Yu, X., MacDonald, R.J., Civin, C.I., Real, F.X., Pack, M.A., Ball, D.W., and Leach, S.D. (2004) Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development (Cambridge, England). 131(17):4213-4224
Lin, J.W., Biankin, A.V., Horb, M.E., Ghosh, B., Prasad, N.B., Yee, N.S., Pack, M.A., and Leach, S.D. (2004) Differential requirement for ptf1a in endocrine and exocrine lineages of developing zebrafish pancreas. Developmental Biology. 270(2):474-486

Miyamoto Y, et al. Notch mediates TGF?-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3:565-576, 2003.

Esni F, et al. Origin of exocrine pancreatic cells from nestin-positive precursors in developing mouse pancreas. Mechanisms of Development, 121:15-25, 2004.

Prasad N, Biankin AV, Fukushima N, Maitra A, Dhara S, Elkahloun AG, Hruban RH, Goggins M, Leach SD. Gene expression profiles in pancreatic Intraepithelial neoplasia reflect the effects of hedgehog signaling on pancreatic ductal epithelial cells. Cancer Research 65:1619-1626 (2005).

Means AL, Meszoely IM, Suzuki K, Miyamoto Y, Means AL, Rustgi AK, Coffey RJ, Stoffers DA, Leach SD. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development, 132: 3767-3776, 2005.

Ghosh B, Leach SD. Interactions between Hairy/Enhancer of Split-related proteins and the pancreatic transcription factor Ptf1-p48 modulate function of the PTF1 transcriptional complex. Biochem. J., 393:679-685, 2006.

Desai B, De Leon D, Farzad C, Hong N, Leach SD, Stoffers DA. Pre-existing acinar cells contribute to acinar cell but not beta cell regeneration. J. Clin. Invest. 117:971-977, 2007.

Habbe N, Shu G, Meguid RA, Fendrich V, Chen H, Feldmann G, Stoffers DA, Koneizcny S*, Leach SD*, Maitra A*. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18913-8, 2008, (* indicates co-senior authors).

Jones S, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analysis. Science, 26:1801-1806, 2008.

Fendrich V, Esni F, Garay MV, Feldmann G, Habbe N, Jensen JN, Dor Y, Stoffers D, Jensen J, Leach SD, Maitra A. Hedgehog signaling is required for effective regeneration of exocrine pancreas. Gastroenterology, 135(2):621-631, 2008.

Wescott MP, Rovira M, Reichert M, von Burstin J, Means A, Leach SD, Rustgi AK. Pancreatic Ductal Morphogenesis and the Pdx-1 Homeodomain Transcription Factor. Mol Biol Cell. 2009 Nov;20(22):4838-44.

Rovira M, Scott SG, Liss AS, Jensen J, Thayer SP, Leach SD. Isolation and characterization of centroacinar / terminal ductal progenitor cells in adult mouse pancreas. Proc Natl Acad Sci U S A. 2010; 107:75-80; doi:10.1073/pnas.0912589107.

Rhim, AD, Mirek ET, Aiello NM, Maitra, A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi, AK, Vonderheide RH, Leach SD, Stanger, BZ. EMT and Dissemination Precede Pancreatic Tumor Formation. Cell 148: 349-361, 2012; doi 10.1016/j.cell.2011.11.025