John P. Lynch

faculty photo
Associate Professor of Medicine
Department: Medicine
Graduate Group Affiliations

Contact information
421 Curie Blvd./912 BRB
Philadelphia, PA 19104
Office: 2158980155
Fax: 2155732024
Education:
B.A. (Chemistry)
University of Pennsylvania , 1987.
MD, PhD (Medicine, Developmental Biology)
University of Connecticut, 1994.
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Description of Research Expertise

Research Interests

1. Mechanisms of intestinal metaplasia of the esophagus (Barrett’s esophagus) and stomach, with a focus on developing novel cell culture and animal models for this disorder.
2. Role of autophagy in the pathogenesis of Barrett’s esophagus, progression to neoplasia, and resistance to therapies.
3. Modeling the effects of Cox-2 activity on oxidative stress and DNA damage in the esophagus.
4. Identification of cells and factors contributing to the intestinal stem cell niche, and their response to injury and disease conditions.
5. Live-cell imaging studies of intestinal stem cell and crypt niche cell interactions, crypt fissioning, mitosis, and early events in neoplastic transformation by confocal microscopy.
6. Role of the intestine-specific transcription factor Cdx2 in promoting intestinal stem cell identity


Description of Research



Barrett’s Esophagus Focus:
Esophageal adenocarcinoma (EAC) has been the fastest rising malignancy in the U.S.. Several conditions increase the risk for the development of EAC, including obesity, smoking, diet, acid reflux, and, most significantly, Barrett's esophagus (BE). BE occurs at the gastroesophageal (GE) junction and is the replacement of normal squamous esophageal mucosa with an intestinalized columnar epithelium. It typically arises in response to chronic acid exposure and is associated with acid reflux. Importantly, the histologic precursor lesions and molecular mechanisms underpinning BE pathogenesis remain poorly understood. One reason is the paucity of experimental models for BE. Our research has focused on this problem, and the development of innovative, genetically based and physiologically relevant human cell based 3D organotypic cultures and transgenic mouse models for BE is an important objective of my lab. We are broadly pursuing several strategies including exploring the role of intestine-specific transcription factors like Cdx1, Cdx2, and Hath1, as well contributions by proinflammatory cytokines (IL-1beta), eicosanoids (Cox-2), and autophagy in BE pathogenesis and progression to neoplasia.

Intestinal Stem Cell Focus:
Stem cells are defined by the capacity for long-term self-renewal and multilineage differentiation. Until relatively recently, our understanding of stem cell biology, as well as their role in many human disease processes from aging to cancer, has been rather limited. Moreover, interest in harnessing the stem cell’s capacity for self-renewal to promote organ and tissue regeneration cuts across many medical disciplines. Genetic studies have identified several robust markers for stem cell populations in the intestine. These advances now make it possible to isolate stem cell populations for more advanced molecular investigations and ex vivo culture. Recently we have begin using live cell confocal microscopy to investigate how the intestinal stem cell niche is established, the relationship between niche and stem cells, how intestinal crypts fission, how stem cells undergo mitosis, and early events in neoplastic transformation. In conjunction with these exploratory studies, we are developing human multi-cell based 3D culture systems in which we can model inflammatory conditions of the gut as a method of studying physiologically the effects of oxidative stress and mitochondrial dysfunction on stem cell biology and stem cell DNA damage.



Lab personnel:
Mary Ann Crissey--Research Specialist and Lab Manager
Jianping Kong PhD--Senior research Investigator
James Bortner PhD--Post Doctoral FellowDoctoral Fellow
Kira Hartman PhD--Post Doctoral FellowDoctoral Fellow
Hong Sai--Research Specialist



Recent Publications:
1. Stairs, D. B., Nakagawa, H., Klein-Szanto, A., Mitchell, S., Silberg, D., Tobias, J.W., Lynch, J. P., Rustgi, A. K.; “Cdx1 and c-myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's Esophagus” PloS ONE 2008;3(10):e3534; PMCID: PMC2568822.

2. Kong, J., Isariyawonse, B.K., Ezaki, T., Nakagawa, N., Silberg, D.G., Rustgi, A.K., Lynch, J.P.; “Induction of Intestinalization in Human Esophageal Keratinocytes is a Multi-step Process.” 2008. Carcinogenesis; 2009 Jan;30(1):122-30; PMCID: PMC2722140

3. Kong, J., Stairs, D.B., Lynch, J.P.; “Modeling Barrett’s Esophagus” Published report in Barrett’s Metaplasia; A Biochemical Society Focused Meeting held at University of Bath, Bath, U.K., 17–18 September 2009. In Biochemical Society Transactions 2010 Apr;38(2):321-6. PMID: 20298176

4. Guo, R.G., Lee, H., Funakoshi, S., Kong, J., Crissey, M.S., Lynch, J.P.; “The intestine-specific transcription factor Cdx2 inhibits β-catenin/TCF transcriptional activity by disrupting the β-catenin/ TCF protein complex “. Carcinogenesis 2010 Feb;31(2):159-66. PMCID: PMC2812568

5. Huo, X., Zhang, H.Y., Zhang, X., Lynch, J.P., Strauch, E.D., Wang, J.Y., Hormi-Carver, K., Spechler, S.J., Souza, R.F.; “Differences in CDX-2 Expression after Exposure to Acid and Bile Salts in Esophageal Squamous Cell Lines from GERD Patients with and without Barrett’s Esophagus.” Gastroenterology 2010 Jul;139(1):194-203.e1 PMCID: PMC2902607

6. Sepulveda, A.R., Lynch, J.P.; “Chronic Inflammation and Genetic Instability in Gastrointestinal Cancers” in Cancer Genome and Tumor Microenvironment, Andrei Thomas-Tikhonenko, Editor. 2010 Springer, New York, NY. P.351-398

7. Funakoshi, S., Kong, J., Crissey, M.S., Dang, D., Dang, L., Lynch, J.P; “Cdx2 induces E-cadherin function by promoting E-cadherin localization to the cell surface” Am J Gastrointest Liver Physiol. (Editorial Highlight) 2010 Nov;299(5):G1054-67. PMCID: PMC2993167

8. Verzi, M.P., Hatzis, P., Philips, J., Sulahian, R., Schuijers, J., Freed, E., Brown, M.A., Lynch, J.P., Dang, D.T., Clevers, H., Liu, X.S., Shivdasani, R.A.; “TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-elements” Proc Natl Acad Sci USA 2010 Aug 24;107(34):15157-62. PMCID: PMC2930576

9. Stairs, D.B., Kong, J., Lynch, J.P.; “Cdx genes, inflammation, and the pathogenesis of intestinal metaplasias” in “Molecular Biology of Digestive Organs.” Editor: Klaus Kaestner. Series Progress in Molecular Biology and Translational Science. 2010;96:231-70. PMID:21075347

10. Crissey, M.S., Guo, R.J., Funakoshi, S., Liu, J., Kong, J., Lynch, J.P.: "Cdx2 Levels Modulate Intestinal Epithelium Maturity and Paneth Cell Development". Gastroenterology 140(2): 517-528, 2011 Notes: Editor's pick for the February 2011 issue. PMCID: PMC3031739

11. Kong, J., Crissey, M.S., Funakoshi, S., Kreindler, J.L., and Lynch, J.P.: "Ectopic Cdx2 expression in murine esophagus models early events in Barrett's esophagus. " PloS ONE 6(4): e18280, April 2011. PMCID: PMC3071814

12. Kong, J., Crissey, M.S., Stairs, D.B., Sepulveda, A.R., and Lynch, J.P.: Cox2 and β-catenin/TCF signaling intestinalize human esophageal keratinocytes when cultured under organotypic conditions. Neoplasia 2011 Sep;13(9):792-805. PMCID: PMC3182272

13. Kong, J., Crissey, M.S., Sepulveda, A.R., and Lynch, J.P.: Math1/Atoh1 contributes to intestinalization of esophageal keratinocytes by inducing the expression of Muc2 and Keratin-20. Digestive Diseases and Sciences 57(4): 845-857; 2012 PMCID: PMC3407817 [Available on 2013/4/1]

14. McAfee, Q.; Zhang, Z.; Samanta, A.; Levi, S.; Ma, X., Piao, S.; Lynch, J.P.; Uhera, T.; Sepulveda, A.R.; Davis, L.; Winkler, J.D.; Amaravadi, R.K.: A novel autophagy inhibitor with single agent antitumor activity reproduces the phenotype of a genetic autophagy deficiency Proceedings of the National Academy of Science 2012 PMCID: PMC3361415

15. Stelzner, M., Helmrath, M., Dunn, J.C.Y., Henning, S.J., Houchen, C.W., Kuo, C., Lynch, J.P., Li, L., Magness, S.T., Martin, M.G., Wong, M., Yu, J. for the NIH Intestinal Stem Cell Consortium: A Nomenclature for Intestinal In Vitro Cultures. American J. Phys, Gastrointestinal and Liver April 2012 2012 Jun;302(12):G1359-63 PMCID: PMC3378093

16. Hamilton, K. E., Crissey, M.S., Lynch, J.P., Rustgi, A.K.: Culturing adult stem cells from mouse small intestinal crypts Cold Spring Harbor Laboratory Press. (In Press)

Description of Clinical Expertise

Gastroenterology

Selected Publications

Xiao F, Crissey MS, Lynch JP, Silberg DG, Suh ER: Intestinal Metaplasia with a High-Salt Diet Induces Epithelial Proliferation and Alters Cell Composition in the Gastric Mucosa of Mice. Cancer Biol Ther. Epub, 6(4): 669-75, June 2005.

Lynch JP, and Rustgi AK: Mechanisms of GI Malignancies. Physiology of the Gastrointestinal Tract, Johnson LR, Barret KE, Gishan FK, Merchant JL, Said HM. Elsevier: San Diego, CA (eds.). Page: 477-498, 2006.

Ezaki T, Guo RJ, Reynolds A, Lynch JP: The Homeodomain Transcription Factors Cdx1 and Cdx2 Induce E-cadherin Adhesion Activity by Reducing beta- and p120-catenin Tyrosine Phosphorylation. Am J Physiol Gastrointest Liver Physiol 293: G54-G65, 2007.

Hegde SR, Sun W, and Lynch JP: Systemic and Targeted Therapy for Advanced Colon Cancer. Expert Review in Gastroenterology and Hepatology 2(1): 135-149, February 2008.

Kong J, Isariyawonse BK, Ezaki T, Nakagawa H, Silberg DG, and Lynch JP: Induction of Intestinalization in Human Esophageal Keratinocytes is a Multi-step Process. Carcinogenesis 30(1): 122-130, Jan 2009 Notes: Epub 10/08.

Stairs DB, Nakagawa H, Klein-Szanto A, Mitchell S, Silberg DG, Tobias JW, Lynch JP, Rustgi AK: Cdx1 and c-myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's Esophagus. PloS ONE 3(10): e3534, October 2008.

Sepulveda AR, and Lynch JP: Chronic Inflammation and Genetic Instability in Gastrointestinal Cancers. Cancer Genome and Tumor Microenvironment, Springer. Andrei Thomas-Tikhonenko (eds.). Springer, New York, NY. Page: P.351-398, 2010.

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Last updated: 04/03/2014
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