Steven Douglas Leach, MD

Research Summary

Dr. Leach's laboratory studies pancreatic progenitor cells using both mouse and zebrafish model systems. His group has made important contributions regarding the normal and abnormal regulation of these cells in a variety of contexts, including pancreatic development, pancreatic regeneration, and pancreatic neoplasia. In particular, work from his group has revealed previously unrecognized plasticity among fully differentiated pancreatic cell types, allowing a variety of different cells to act not only as "on- demand" progenitors, but also as cells of origin for pancreatic neoplasia. More recently, Dr. Leach''s group has also identified a novel dedicated progenitor population residing in adult mouse pancreas, and localized these cells to a centroacinar/terminal ductal position. Current studies in the lab include:

* Further characterization of centroacinar progenitor cells 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

Journal Citations

Baillargeon, J.; Platz, E.A.; Rose, D.P.; Pollock, B.H.; Ankerst, D.P.; Haffner, S.; Higgins, B.; Lokshin, A.; Troyer, D.; Hernandez, J.; Lynch, S.; Leach, R.J.; Thompson, I.M. Obesity, adipokines, and prostate cancer in a prospective population-based study. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1331-1335.

Ghosh, B.; Leach, S.D. Interactions between hairy/enhancer of split-related proteins and the pancreatic transcription factor Ptf1-p48 modulate function of the PTF1 transcriptional complex. Biochem J. 2006 Feb 1;393(Pt 3):679-685.

Biankin, S.A.; Collector, M.I.; Biankin, A.V.; Brown, L.J.; Kleeberger, W.; Devereux, W.L.; Zahnow, C.A.; Baylin, S.B.; Watkins, D.N.; Sharkis, S.J.; Leach, S.D. A histological survey of green fluorescent protein expression in 'green' mice: implications for stem cell research. Pathology. 2007 Apr;39(2):247-251.

Parekh, D.J.; Ankerst, D.P.; Baillargeon, J.; Higgins, B.; Platz, E.A.; Troyer, D.; Hernandez, J.; Leach, R.J.; Lokshin, A.; Thompson, I.M. Assessment of 54 biomarkers for biopsy-detectable prostate cancer. Cancer Epidemiol Biomarkers Prev. 2007 Oct;16(10):1966-1972.

Pisharath, H.; Rhee, J.M.; Swanson, M.A.; Leach, S.D.; Parsons, M.J. Targeted ablation of beta cells in the embryonic zebrafish pancreas using E. coli nitroreductase. Mech Dev. 2007 Mar;124(3):218-229.

Cheng, W.C.; Leach, K.M.; Hardwick, J.M. Mitochondrial death pathways in yeast and mammalian cells. Biochim Biophys Acta. 2008 Jul;1783(7):1272-1279.

Davison, J.M.; Woo Park, S.; Rhee, J.M.; Leach, S.D. Characterization of Kras-mediated pancreatic tumorigenesis in zebrafish. Methods Enzymol. 2008 June;438:391-417.

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

Garonzik Wang, J.M.; Leach, S.D. Truncal sarcomas and abdominal desmoids. Surg Clin North Am. 2008 Jun;88(3):571-582, vi-vii.

Habbe, N.; Shi, G.; Meguid, R.A.; Fendrich, V.; Esni, F.; Chen, H.; Feldmann, G.; Stoffers, D.A.; Konieczny, S.F.; Leach, S.D.; 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):18913-18918.

Jones, S.; Zhang, X.; Parsons, D.W.; Lin, J.C.; Leary, R.J.; Angenendt, P.; Mankoo, P.; Carter, H.; Kamiyama, H.; Jimeno, A.; Hong, S.M.; Fu, B.; Lin, M.T.; Calhoun, E.S.; Kamiyama, M.; Walter, K.; Nikolskaya, T.; Nikolsky, Y.; Hartigan, J.; Smith, D.R.; Hidalgo, M.; Leach, S.D.; Klein, A.P.; Jaffee, E.M.; Goggins, M.; Maitra, A.; Iacobuzio-Donahue, C.; Eshleman, J.R.; Kern, S.E.; Hruban, R.H.; Karchin, R.; Papadopoulos, N.; Parmigiani, G.; Vogelstein, B.; Velculescu, V.E.; Kinzler, K.W. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008 Sep 26;321(5897):1801-1806.

Le, D.; Jaffee, E.M.; Laheru, D.A. Development of Vaccine Therapy for Pancreas Cancer. In: Andrew Lowy, S.L., Philip Philip, editor. 1 ed, Pancreatic Cancer. New York: Springer; 2008.

Park, S.W.; Davison, J.M.; Rhee, J.; Hruban, R.H.; Maitra, A.; Leach, S.D. Oncogenic KRAS induces progenitor cell expansion and malignant transformation in zebrafish exocrine pancreas. Gastroenterology. 2008 Jun;134(7):2080-2090.

Parsons, M.J.; Pisharath, H.; Yusuff, S.; Moore, J.C.; Siekmann, A.F.; Lawson, N.; Leach, S.D. Notch-responsive cells initiate the secondary transition in larval zebrafish pancreas. Mech Dev. 2009 Oct;126(10):898-912.

Kent, O.A.; Chivukula, R.R.; Mullendore, M.; Wentzel, E.A.; Feldmann, G.; Lee, K.H.; Liu, S.; Leach, S.D.; Maitra, A.; Mendell, J.T. Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway. Genes Dev. 2010 Dec 15;24(24):2754-2759.

Rovira, M.; Scott, S.G.; Liss, A.S.; Jensen, J.; Thayer, S.P.; Leach, S.D. Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):75-80.