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Andres J.P. Klein-Szanto, MD, PhD

Andres J.P. Klein-Szanto, MD, PhD
About

Professor

Director, Histopathology Facility

Research Program

Education, Training & Credentials

Educational Background

  • PhD, Pathology, University of Buenos Aires School of Medicine, Argentina, 1970
  • MD, Medicine, University of Buenos Aires School of Medicine, Argentina, 1965

 

Memberships

  • American Association for the Advancement of Science
  • American Association for Cancer Research
  • US and Canadian Academy of Pathology
  • European Society of Pathology
  • Associate Editor, Acta Odontologica Latinoamericana, 1984-present
  • Associate Editor, Molecular Carcinogenesis, 1994-present
  • Member, External Advisory Committee, Wistar/Penn Skin SPORE, 2001-2004
  • Ad Hoc Reviewer for the Cancer Etiology Study Section Section, National Institutes of Health, Division of Research Grants, Bethesda, MD, 2004-2008 
Research Profile

Research Program

Research Interests

  • Role of the Pro-protein convertases furin and PACE-4 in cancer progression.
  • Inhibition of Furin and other Pro-protein convertases as potential cancer therapy.
  • Pathobiology and pathogenesis of skin, oral mucosa and esophageal cancer.

Lab Overview

Tumor progression is a chain of cellular and molecular events that occur gradually during the development of neoplasia. We are studying the role of pro-protein convertases (PCs) such PACE-4 and furin during the early and late stages of tumor progression. These enzymes activate cancer related biomolecules that regulate cell proliferation, cell adhesion and invasion. Over-expression of PCs correlates with aggressive tumor features both in mouse models and in human tumors. This has been demonstrated in our laboratory using tumor cells derived from lung, esophagus, ovarian and oral malignant tumors. Inhibition of PCs can be obtained by using competitive inhibitors such as chloro-methyl-ketone (CMK). This inhibitor decreases and even abolishes the invasive/malignant phenotype of tumor cells by inhibiting the activation of invasion and metastasis-associated gene products such as MT1-MMP, stromelysin 3, TGF-β and IGFR1. CMK was also used in vivo by topical skin administration. Using this modality we were able to decrease 40% the number of chemically-induced mouse skin cancers as well as diminish 60% the respective tumor volumes. Similarly using CMK and RNA interference we have been able to decrease in vitro and in vivo growth of human cancer cells. Partly because of these dicoveries, proprotein convertases have been recognized as targets for cancer therapy and several clinical trials are being conducted in multiple centers. These trials use furin interference RNA in combination with GMCSF (granulocyte-macrophage colony-stimulating factor) to down regulate furin and decrease furin-substrate mediated pro-tumorigenic effects including immunosuppression and cell growth.

My laboratory collaborates with a multidisciplinary team from the University of Pennsylvania, Harvard University and The Medical University of South Carolina that had join forces to study mechanisms of esophageal carcinogenesis. We focus on the histopathology and immunohistochemistry of several projects. For example, in vitro/invivo experiments have shown the role of cyclin D1 regulation and Fbx4 mutations in esophageal carcinogenesis. Specifically, SCFFBX4-aB crystallin E3 ligase maintains threshold levels of the cyclin D1/CDK4 kinase critical for esophageal cell growth and homeostasis. Other studies on mechanisms of esophageal cancer include the role of periostin, Notch-1, Notch-3, WNT10A as well as several other biomolecules involved in autophagy and tumor microenvironment. 

People

Jirong Zhang, PhD

Scientific Technician II

Room: C417
215-728-3155
Publications

Selected Publications

Klein-Szanto A.J., Zhang J., and Bassi D.E.  Proprotein Convertases in gynecological cancers. Colloquium Series on Protein Activation and Cancer, 1 (2): 1-43, 2012, San Rafael (CA): Morgan & Claypool Life Sciences. DOI: 10.4199/C00065ED1V01Y201208PAC002, ISBN: 9781615044658.

Fu J., Bassi D.E. Zhang J.,  Li T., Cai K.Q., Testa C.L.,  Nicolas E. and Klein-Szanto A.J. Enhanced UV-Induced Skin Carcinogenesis in Transgenic Mice Overexpressing Proprotein Convertases. Neoplasia 15, 169179, 2013. PMC3579319. PubMed

Wong G., Habibollahi P., Heidari P., Lee J., Klein-Szanto A.J., Waldron T.,  Gimotty P., Nakagawa H.,. Taylor P., Wang T., Mahmood U. and Rustgi A.K. Optical imaging of periostin enables early endoscopic detection and characterization of esophageal cancer in mice. Gastroenterol. 144:294-297, 2013. PMC3624041. PubMed

Li Y, Chitnis N, Nakagawa H, Kita Y, Natsugoe S, Yang Y, Li Z, Wasik MA, Klein-Szanto AJ, Rustgi AK, Diehl JA,  PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers. Cancer Discov. 5:288-303, 2015. PMC4355177. PubMed

Bassi D.E., Cenna J., Zhang J., Cukierman E. and Klein-Szanto A.J. Enhanced aggressiveness of benzopyrene-induced squamous carcinomas in transgenic mice overexpressing the proprotein convertase PACE4 (PCSK6). Molec. Carcinogenesis ;54:1122-31, 2015. PMC4240754 PubMed

Tétreault M., Weinblatt D., Dyan Ciolino J,. Klein-Szanto A.J., Sackey B.K., Twyman-Saint Victor C., Karakasheva T., Teal V., Katz.J.P.  Esophageal Expression of Active IκB kinase-β in Mice Upregulates Tumor Necrosis Factor and Granulocyte Macrophage Colony-stimulating Factor, Promoting Inflammation and Angiogenesis. Gastroenterology 150:1609-1619, 2016. PMC4909513

Kadariya Y, Cheung M, Xu J, Pei J, Sementino E, Menges CW, Cai KQ, Rauscher FJ, Klein-Szanto AJ, Testa JR. Bap1 is a bona fide tumor suppressor: genetic evidence from mouse models carrying heterozygous germline Bap1 mutations. Cancer Res. 76:2836-2844, 2016. PMC4873414. PubMed

Bassi DE, Zhang J, Renner C and Klein-Szanto AJP. Targeting proprotein convertases in furin-rich lung cancer cells results in decreased In vitro and In vivo growth. Molec. Carcinogenesis 56:1182-1188, 2017. PubMed

Giroux V, Lento A, Islam M,  Pitarresi JR, Kharbanda  A, Hamilton KE, Whelan K, Long A, Rhoades B, Tang Q, Nakagawa H, Lengner CJ,. Bass AJ, Wileyto EP, Klein-Szanto AJ, Wang TC, Rustgi AK. Novel long-lived esophageal progenitor cells contribute to homeostasis and regeneration. J Clin Investig. (in press).

Klein-Szanto AJ and Bassi DE. Proprotein convertase inhibition: Paralyzing the cell’s master switches.  Biochem Pharmacol. (in press)

 

Additional Publications

My NCBI

This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
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