This Fox Chase professor participates in the Undergraduate Summer Research Fellowship.
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Professor Emeritus
Co-Director, Histopathology Facility
My laboratory collaborates with a multidisciplinary team that study mechanisms of esophageal carcinogenesis. Our lab focuses on the histopathology, immunohistochemistry and image analysis of animal model of esophageal carcinogenesis. Another aspect of our research consists on evaluating human and murine esophageal organoids that may help in finding effective tools to find novel approaches to cancer therapy.
My laboratory has studied 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.
Recently, we have found together with our collaborators in Munster, Germany that the overexpression of PACE 4 (PCSK6) in melanoma cell lines and in human melanoma tissue is directly related to a significant increased cell proliferation, MMP-2 production, gelatinase activity and migratory capacity of cell lines in vitro compared with sham-transfected cells. In vivo, elevated PACE4 expression resulted in significantly increased tumor growth when PACE-transfected cells were inoculated sc. into immunodeficient mice. In the majority of 45 human primary melanomas and melanoma metastases investigated, PACE4 immunoreactivity was detectable, while it was absent in in situ melanomas. These results point to PACE4 as a regulator of melanoma cell aggressiveness and a possible target for therapy.
The PC studies have almost been concluded and my laboratory is now mostly devoted to the evaluation of models of GI cancer especially esophagus, oral cavity and pancreas using genetically modified animal models and 3D organoid cultures of both animal models and human cancers.
My laboratory collaborates with a multidisciplinary team from the H. Irving Comprehensive Cancer Center of Columbia University, Harvard University, NYU, and Case Western Reserve University that had join forces to study mechanisms of esophageal carcinogenesis. Our lab focuses on the histopathology, immunohistochemistry and image analysis of animal tissues and organoids that may help facilitate characterization as well as, in the specific case of human organoids, be an effective tool to find new approaches to novel therapies.
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. 127:2378-2391, 2017. PMC5451220.
Klein-Szanto AJ and Bassi DE. Proprotein convertase inhibition: Paralyzing the cell’s master switches. Biochem Pharmacol. 140:8-15, 2017. PMC5586041.
Karakasheva T.A., Lin E.W., Tang Q., Qiao E., Waldron T.J., Soni M. , Klein-Szanto A.J., Sahu V., Basu D., Giaccone Z., Walker S.R., Frank D.A., Wileyto E.P., Long Q., Diehl J.A., Wong K.K., Bass A.J., Rustgi A.K.. IL-6 mediates cross-talk between activated fibroblasts and tumor cells in the tumor microenvironment: Applications in therapeutic intervention.
Nature Comm 8(1):1758. doi: 10.1038/s41467-017-015009, 2017. PMC5700926.
Kasagi Y., Chandramouleeswaran P. M., Whelan K., Tanaka T., Giroux V., Mehda S., Wang J., Tobias J.W., Benitez A., DeMarshall M., Hamilton K.E., Falk G., Spergel J., Klein-Szanto A.J., Rustgi A.K., Muir. A. B., Nakagawa H. The esophageal organoid system reveals functional interplay between Notch and cytokines in reactive epithelial changes. Cellular and Molecular Gastroenterology and Hepatology 5: 333–352, 2018. PMC5852293.
Giroux V, Stephan J, Chatterji P, Rhoades B, Wileyto EP, Klein-Szanto AJ, Lengner CJ, Hamilton KE, Rustgi AK. Mouse Intestinal Krt15+ Crypt Cells Are Radio-Resistant and Tumor Initiating. Stem Cell Reports. 10:1947-1958, 2018. PMC5993649.
Reichert M, Bakir B, Moreira L, Pitarresi JR, Feldmann K, Simon L, Suzuki K, Maddipati R, Rhim AD, Schlitter AM, Kriegsmann M, Weichert W, Wirth M, Schuck K, Schneider G, Saur D, Reynolds AB, Klein-Szanto AJ, Pehlivanoglu B, Memis B, Adsay NV, Rustgi AK. Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer. Dev. Cell 18;45:696-711,2018. PMC6011231.
Kijima T, Nakagawa H., Shimonosono M., Chandramouleeswaran P., Hara T., Sahu V., Kasagi Y., Kikuchi O., Tanaka K., Giroux V., .Muir A.M.,Whelan K., Ohashi S., Naganuma S., Klein-Szanto A.J., Shinden Y., Sasaki K., Omoto I., Kita Y., Muto M., Bass A., Diehl J.A., Ginsberg G., Avadahani N., Basu D. , Rustgi A.K., Natsugoe S. Three-dimensional organoids reveal therapy resistance of esophageal andoropharyngeal squamous cell carcinoma cells. Cellular and Molecular Gastroenterology and Hepatology 7: 73-91, 2018. PMC6260338.
Guha M , Srinivasan S, Sheehan M, Kijima T., Ruthel G., Whelan K, Tanaka K, Klein-Szanto A.J., Chandramouleeswaran P., Nakagawa H., and Avadhani N..Esophageal 3D organoids of MPV17-/- mouse model of mitochondrial DNA depletion show epithelial cell plasticity and telomere attrition. Oncotarget 10(58):6245–6259, 2019. PMC6817447.
Karakasheva T., Kijima T., Shimonosono M., Maekawa H., Cruz-Acuna R., Gabre J., Giroux V., Sangwan V. Whelan K., Hamilton K., Muir A.B., Natsugoe S., Klein-Szanto A.J., Ginsberg G., Falk G., Abrams J., Que J., Ferri L., Diehl J.A.,. Bass A., Wang T., Rustgi A.K., Nakagawa H. Generation and Characterization of Patient-Derived Head and Neck, Oral, and Esophageal Cancer Organoids. Curr Protoc Stem Cell Biol. 2020 Jun;53(1):e109. doi: 10.1002/cpsc.109. PMC7350550.
Weishaupt C, Mastrofrancesco A, Metze D, Kemper B, Stegemann A, Picardo M, Klein-Szanto AJP, Böhm M. Paired Basic Amino Acid-cleaving Enzyme 4 (PCSK6): An Emerging New Target Molecule in Human Melanoma. Acta Derm Venereol. 2020 May 28;100(10): adv00157. doi: 10.2340/00015555-3525. PMC in progress.
Francescone R, Barbosa Vendramini-Costa D, Franco-Barraza J, Wagner J, Muir A, Lau AN, Gabitova L, Pazina T, Gupta S, Luong T, Rollins D, Malik R, Thapa RJ, Restifo D, Zhou Y, Cai KQ, Hensley HH, Tan Y, Kruger WD, Devarajan K, Balachandran S, Klein-Szanto AJ, Wang H, El-Deiry WS, Vander Heiden MG, Peri S, Campbell KS, Astsaturov I, Cukierman E. Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression. Cancer Discov. 2020 PMC in progress.
This Fox Chase professor participates in the Undergraduate Summer Research Fellowship.
Learn more about Research Volunteering.
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