Description of Research Expertise:
Oncogenes, tumor suppressor genes, tumor microenvironment, tumor metastasis, molecular genetics of GI cancers (colon, pancreatic, upper GI)
Key words: Cancers: esophageal, pancreatic, 3D cultures, mouse models
Description of Research
Our laboratory has had long-standing thematic interests in the cell-type and tissue-type specific actions of certain oncogenes (cyclin D1, EGFR) and tumor suppressor genes (p53, p120 catenin) in modulating the initiation, progression and invasion of gastrointestinal cancers, especially upper GI, pancreatic and colon. To that end, we employ novel three-dimensional cell culture systems (mouse and human origins) and genetically-engineered mouse models to investigate molecular mechanisms. These projects are translated into the objectives of improving molecular diagnostics and experimental therapeutics in patients.
Our research is funded through an NCI program project entitled "Mechanisms of Esophageal Carcinogenesis", NIH R01 grant on pancreatic cancer, and NIH R01 grant on colon cancer. Students and postdoctoral fellows are supported in didactic venues and conferences, present at national meetings, and have obtained national grant fellowships when applicable.
1. To understand the role of oncogenes and tumor suppressor genes (p53, p120catenin) in the tumor microenvironment as they relate to tumor cell migration and invasion in GI cancers, using 3D culture and mouse models.
2. To define mechanisms underlying cell lineage fate decisions during pancreatic development and cancer
3. To functionally characterize RNA binding proteins in colon cancers.
4. To functionally characterize stem cells in the upper GI tract.
5. Mechanisms underlying tumor metastasis and metastatic organotropcan.
Sarah Andres, PhD, Postdoctoral Fellow (NIH F32 Fellowship)
Basil Bakir, MD PhD student
Priya Chatterji, PhD student
Veronique Giroux, PhD, Postdoctoral Researcher (Canadian government fellowship)
Tatiana Karakasheva, PhD student, CAMB (thesis project)
Benoit Marchand, PhD, Postdoctoral Fellow
Leticia Moreira, PhD (Spanish government fellowship)
Jason Pitaressi, PhD
Mizuno Rei, MD, Postdoctoral Fellow
Ben Rhoades, M.B., Research specialist and lab manager
Tracy Tang, PhD student
Recently in Lab:
Daniel Abravanel, University of Pennsylvania, Rotating MD, PhD Student
Claudia Andl, PhD, Research Associate (recipient of NIH K01 grant and AGA Research Scholar Award), Associate Professor, University of Central Florida
Amy Demicco,University of Pennsylvania, Rotating PhD Student
Brent Fargnoli, University of Pennsylvania undergraduate student (University and Ben Franklin Scholar)
Christie Gutierrez, University of Pennsylvania, Undergraduate student (AGA student fellowship)
Katharine D. Grugan, PhD,Postdoctoral fellow (recipient of NIH F32 fellowship). Currently, at Janssen
Christopher Hahn, BA, Research Specialist
Kathryn Hamilton, PhD, Research Associate (NIH K01 and CCFA grants), currently Assistant Professor of Pediatrics, Children's Hospital of Philadelphia
Steffen Heeg, MD, Postdoctoral Researcher (German Cancer Society fellowship)
Phillip Hicks, Research Specialist. Now VMD-PhD student at University of Pennsylvania
Cameron Johnstone, PhD, Research Investigator (recipient of American Association for Cancer Research fellowship and Department of Defense grant). Now at Peter McCallum Cancer Institute, Melbourne, Australia
Elizabeth Kennedy, University of Pennsylvania, Rotating PhD student
Catrina King, PhD Received her PhD in Dec 2010; graduate of VMD program. Completed residency at Columbia University Medical Center
Emma Lundsmith, medical student (HHMI fellowship)
Blair Madison, PhD, Research Associate (NIH K01 grant), now Assistant Professor of Medicine at Washington University
Carmen Z. Michaylira, PhD, Postdoctoral fellow (recipient of NIH F32 fellowship)
Charles Miller, University of Pennsylvania, Undergraduate student, MD-PhD student at Rutgers/Princeton Universities
Perry Mongroo, PhD, Postdoctoral fellow
Keeley Mui, University of Pennsylvania, Rotating PhD Student
Max Reichert, MD, Postdoctoral Researcher (National Pancreas Foundation fellowship), Faculty in Munich, Germany
Anna-Sophie Rich, University of Pennsylvania, Medical Student (recipient of NIH/NIDDK fellowship)
Doug Stairs, PhD, Now Assistant Professor of Pathology, Hershey Medical Center (Recipient of NIH F32 fellowship and NIH K99-R00 grant in lab)
Shigetsugu Takano, MD, Visiting Assistant Professor
Jonathan Toung, University of Pennsylvania, Undergraduate Student (Vagelos Scholar)
Maria Vega, PhD student, CAMB (thesis project; NIH T32 training grant), postdoctoral fellow at Princeton University
Johannes von Burstin, MD, Postdoctoral fellow (recipient of DFG fellowship). At Technical University, Munich, Germany
Todd Waldron, PhD, Postdoctoral fellow (NIH F32 fellowship)
Melanie P. Wescott, PhD, Postdoctoral fellow (recipient of National Pancreas Foundation fellowship)
Louise Wang, University of Pennsylvania, undergraduate student (NIH fellowship). Now Medical Intern at University of Pennsylvania
Rafi Winograd, University of Pennsylvania Rotating MD PhD student
Gabrielle Wong, PhD student, CAMB (thesis project; NIH T32 training grant). Now postdoctoral fellow at Dana Farber Cancer Institute
Bihui (Claudia) Xu, University of Pennsylvania, rotating PhD student
Yao Yao, University of Pennsylvania, Rotating DVM PhD Student
Lin EW, Karakasheva TA, Lee DJ, Lee JS, Long Q, Bass AJ, Wong KK: Comparative transcriptomes of adenocarcinomas and squamous cell carcinomas reveal molecular similarities that span classical anatomic boundaries PLoS Genet 13(8) : e1006938,2017.
Giroux V, Lento AA, Islam M, Pitarresi JR, Kharbanda A, Hamilton KE, Whelan KA, Long A, Rhoades B, Tang Q, Nakagawa H, Lengner CJ, Bass AJ, Wileyto EP, Klein-Szanto AJ, Wang TC: Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration J Clin Invest 127(6) : 2378-2391,2017.
Dotto GP: Squamous Cell Cancers: A Unified Perspective on Biology and Genetics Cancer Cell 29(5) : 622-37,2016.
Takano S, Reichert M, Bakir B, Das KK, Nishida T, Miyazaki M, Heeg S, Collins MA, Barchand B, Hicks PD, Maitra A: Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization Genes and Development 30(2) : 233-47,2016.
Madison BB, Liu Q, Zhong X, Hahn CM, Lin N, Emmett MJ, Stanger BZ, Lee JS: LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7. Genes and Development 27(20) : 2233-45,2013.
Reichert M, Takeano, S, von Burstin, J, Kim, SB, Lee, JS, Stansbury, KI, Hahn, C, Heeg, S, Schneider, G, Rhim, A, Stanger, BZ, Rustgi: The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis Genes & Development 27 : 288-300,2013.
Kalabis J, Wong GS, Vega ME, Natsuizaka M, Robertson ES, Herlyn M, Nakagawa H: Isolation and characterization of mouse and human esophageal epithelial cells in 3D organotypic culture Nature Protocols 7 (2): 235-46,2012.
Quante M, Bhagat G, Abrams JA, Marache F, Good P, Lee MD, Lee Y, Friedman R, Asfaha S, Dubeykovskaya Z, Mahmood U, Figueiredo JL, Kitajewski J, Shawber C, Lightdale CJ, Rustgi AK: Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell 21 (1): 36-51,2012.
Stairs DB, Bayne LJ, Rhoades B, Vega ME, Waldron TJ, Kalabis J, Klein-Szanto A, Katz JP, Diehl JA, Reynolds AB, Vonderheide RH: Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a tumor suppressor gene Cancer Cell 19 (4): 470-83,2011.
Kalabis J, Oyama K, Okawa T, Nakagawa H, Michaylira CZ, Stairs DB, Figueiredo JL, Mahmood U, Diehl JA, Herlyn M: A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification J Clinical Investigation 118 (12): 3860-9,2008.
Okawa, T., Michaylira, C.Z., Kalabis, J., Stair, D., Nakagawa, H., Andl, C., Claudia, D., Johnstone, C.N., Andres, J., Klein-Szanto, A.J., El-Deiry, W.S., Cukierman, E., Herlyn, M., Rustgi: The functional interplay between EGFR overexpression, hTERT activation and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induce tumor development, invasion and differentiation Genes & Development 21 : 2788-803,2007.
Deramaudt TB, Takaoka M, Upadhyay R, Bowser MJ, Porter J, Lee A, Rhoades B, Johnstone CN, Weissleder R, Hingorani SR, Mahmood U: N-cadherin and keratinocyte growth factor receptor mediate the functional interplay between Ki-RASG12V and p53V143A in promoting pancreatic cell migration, invasion, and tissue architecture disruption Mol Cell Biol 26 (11): 4185-4200,2006.
Andl CD., Mizushima T., Nakagawa H., Oyama K., Harada H., Chruma K., Herlyn M.: Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo Journal of Biological Chemistry 278 (3): 1824-30,2003.
Opitz OG, Suliman Y, Hahn WC, Harada H, Blum HE: Cyclin D1 overexpression and p53 inactivation immortalize primary oral keratinocytes by a telomerase independent mechanism Journal of Clinical Investigation 108 : 725-732,2001.
Opitz O.G., Harada H., Suliman Y., Rhoades B., Sharpless N.E., Kent R., Kopelovich L., Nakagawa H.: A mouse genetic model of human oral-esophageal cancer Journal of Clinical Investigation 110 : 761-769,2002.
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