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Secondary Faculty
Steven Leach, M.D.
Professor of Surgery, Oncology, and Cell Biology
Johns Hopkins University School of Medicine
733 North Broadway, 471 BRB
Baltimore, MD 21205
Telephone: (Office) 410-955-5765
(Lab) 410-502-6985
Fax: 410-502-1853
Email: stleach@jhmi.edu
Website:
Primary Appt. Department of Surgery
Secondary Appt. Department of Oncology

 

 

 

 

 

 

 

 

 

Research Topic: Pancreatic Progenitor Cells in Development and Disease  
Our lab studies epithelial progenitor cells in developing, regenerating and neoplastic pancreas, using both mouse and zebrafish model systems. By characterizing how pancreatic progenitor cells are regulated, we hope to provide for their eventual therapeutic manipulation, both as probable “cells of origin” for pancreatic cancer, and also as a resource for cell replacement therapy in diabetes.

Current  studies in the lab include the following:

  • Identifying and characterizing a novel progenitor population in adult mouse and zebrafish pancreas

  • Utilizing Cre-mediated cassette exchange to interrogate transcription factor function in developing zebrafish pancreas

  • Using single cell transcriptional profiling to reveal previously unrecognized heterogeneity among pancreatic epithelial cell types

  • Identifying novel targets of the pancreas-specific Ptf1 transcriptional complex, using genome-wide screening techniques

  • Developing a novel in vitro model of pancreatic intra-epithelial neoplasia (PanIN)

  • Further developing zebrafish models of pancreatic cancer, and employing these models to functionally annotate the human pancreatic cancer genome.

Select Publications

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.

Lin JW, et al. Differential requirement for ptf1a in endocrine and exocrine lineages of developing zebrafish pancreas. Developmental Biology 270: 474-486, 2004.

Esni R, et al. Notch inhibits PTF1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development, 131: 4213-4224, 2004.


Means AL, Meszoely IM, Suzuki K, Miyamoto Y, 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.

Provost E, Rhee J, Leach SD.  Viral 2A peptides allow expression of multiple proteins from a single ORF in transgenic zebrafish embryos.  Genesis, 45:625-629 (DOI 10.10002/dvg.20338), 2007.

Davison JM, Park SW, Rhee JM, Leach SD.  Characterization of KRAS-mediated pancreatic tumorigenesis in zebrafish.  Methods in Enzymology, 438:391-417, 2008.

Park SW, Davison JM, Rhee J, Pisharath H, Hruban RH, Maitra A, Leach SD. Oncogenic KRAS induces progenitor cell expansion and malignant transformation in zebrafish exocrine pancreas. Gastroenterology, 134:2080-2090, 2008.

Dong PDS, Provost E, Leach SD, Stainier DYR.  Ptf1a plays a critical role in determining pancreatic endocrine versus exocrine cell fate.  Genes and Development, 22:1445-1450, 2008.

Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW.  Core signaling pathways in human pancreatic cancers revealed by global genomic analysis. Science, 26:1801-1806, 2008.

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 USA, Dec 2;105(48):18913-8. Epub 2008 Nov 21. (* indicates co-senior authors)

Parsons MJ, Pisharath H, Yusuff S, Moore JC, Siekmann AF, Lawson N, Leach SD. Notch-responsive cells initiate the secondary transition in larval zebrafish pancreas. Mech Dev. 2009 126(10):898-912.

Rovira M, Scott SG, Liss AS, Jensen J, Thayer SP, Leach SD. Isolationa and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc Natl Acad Sci U S A. 2010 Jan 5; 107:75-80; doi:10.1073/pnas.0912589107.

 

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Updated: 2/2/11

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