Jaime Modiano, V.M.D, Ph.D. Professor Department of Veterinary Clinical Sciences University of Pennsylvania, 1991, V.M.D., Ph.D. Office phone: 612-625-7436 modiano@umn.edu

Research Interests:

Cancer pathogenesis and cancer immunology

Dr. Modiano's lab is focused on three different research aspects:

1. Heritable Factors that Determine Cancer Risk and Etiology. The goal of this research is to identify heritable factors that contribute to risk, origin, and progression of cancer using naturally occurring diseases of dogs, which closely resemble those seen in people, as well as cultured cells and laboratory animal models that allow us to ask research questions under highly controlled conditions. Our work shows that there are breed-specific patterns of prevalence for non-Hodgkin's lymphoma and other tumors in dogs. More importantly, these tumors also show breed-specific genetic aberrations that reflect the existence of unique risk factors. We predict these risk factors are shared between dogs and humans. Finally, we have used canine hemangiosarcoma and canine non-Hodgkin's lymphoma to verify the cancer stem cell hypothesis in a naturally occurring animal tumor. Current work is aimed at defining how heritable factors influence risk, pathogenesis, and outcomes of human and animal patients with tumors arising from "cancer stem cells."

2. Lymphocyte Negative Regulation. We seek to define mechanisms that control cell cycle entry in lymphocytes. Various transcription factors, including NFATc2 and Tob, appear to control a program of intrinsic negative regulation, which actively maintains lymphocytes in a quiescent (inactive or resting) state. Our goals are to define mechanisms by which these transcription factors sustain quiescence and to understand how they can be enforced or disengaged in physiological or pathological states. For example, we have shown that nicotine-mediated calcium fluxes activate NFATc2 in T cells, increasing their activation threshold. Our data also indicate that nicotinic acetylcholine receptors provide tonic signals that are necessary for survival, and they contribute to calcium signaling in activated T cells. Finally, cumulative, non-redundant defects in negative regulation trigger lymphocyte apoptosis. We are presently testing the hypothesis that autoimmunity and failure of immune surveillance can be driven by defects in lymphocyte negative regulation.

3. Novel Approaches for Cancer Immunotherapy. We seek to characterize properties of immune effector cells that can kill tumors as a means to develop effective protocols for immunotherapy. Our data show that T cell priming requires exposure to tumor in the context of a productive innate immune response, and that disabling T cell negative regulation makes T cells more efficient at infiltrating and killing tumors. We also show that nicotine contributes to angiogenesis, possibly by mobilization of endothelial precursor cells. We have extended these principles to models where treatment of dogs with naturally occurring cancers provides a means to improve the health and well being of companion animals, while translating basic findings into therapeutic applications for human cancer patients.

Selected Publications:

Ritt MG, Mayor J, Wojcieszyn J, Smith R III, Barton CL, Modiano JF. (2000) Sustained nuclear localization of p21/Waf-1 upon growth arrest induced by contact inhibition. Cancer Lett 158, 73-84

Modiano JF, Mayor J, Ball C, Fuentes MS, Linthicum DS. (2000) Cdk4 expression and activity are required for cytokine responsiveness in T cells. J Immunol 165, 6693-6702

Baksh S, Widlund H, Frazer-Abel AA, Du J, Fosmire S, Fisher DE, DeCaprio JA, Modiano JF, Burakoff SJ. (2002) NFATc2-mediated repression of cyclin-dependent kinase 4 expression. Mol Cell, 10, 1071-1081

Khare S, Banai Y, Gokulan K, Linthicum DS, Modiano JF. (2003) Early changes in cellular metabolism of leukemic cell lines upon induction of apoptosis by cytotoxic drugs. Eur J Pharmacol, 465, 23-30

Bianco SR, Sun J, Fosmire SP, Hance K, Padilla M, Ritt MG, Getzy D, Duke RC, Withrow S, Lana S, Matthiesen DT, Dow S, Bellgrau D, Cutter G, Helfand SC, Modiano JF. (2003) Enhancing anti-melanoma immune responses through apoptosis. Cancer Gene Ther, 10, 726-736

Fosmire SP, Dickerson EB, Scott A, Bianco SR, Pettengil M, Meylemans H, Padilla M, Frazer-Abel AA, Akhtar N, Getzy DM, Wojcieszyn J, Breen M, Helfand SC, Modiano JF. (2004) Canine malignant hemangiosarcoma as a model of primitive angiogenic endothelium. Lab Invest, 84, 562-572

Frazer-Abel AA, Baksh S, Fosmire SP, Willis D, Pierce AM, Meylemans H, Linthicum DS, Burakoff SJ, Coons T, Bellgrau D, Modiano JF. (2004) Nicotine activates NFATc2 and prevents cell cycle entry in T cells. J Pharmacol Exp Ther, 311, 758-769

Modiano JF, Lamerato-Kozicki AR, Jubala CM, Coffey D, Borakove M, Schaack J, Bellgrau D. (2004) Fas ligand gene-transfer for cancer therapy. Cancer Therapy 2, 561-570

Modiano JF, Breen M, Burnett RC, Parker HG, Inusah S, Thomas R, Avery PR, Lindblad-Toh K, Ostrander EA, Cutter G, Avery AC. (2005) Distinct prevalence of B and T cell lymphoproliferative diseases among dog breeds is an indicator of heritable risk traits. Cancer Res, 65, 5654-5661

Thomas R, Scott A, Langford C, Fosmire SP, Jubala CM, Lorentzen TD, Hitte C, Karlsson EK, Kirkness E, Ostrander EA, Galibert F, Lindblad-Toh K, Modiano JF, Breen M. (2005) Construction of a 2Mb resolution BAC-microarray for CGH analysis of canine tumors. Genome Res, 15, 1831-1837

Modiano JF, Breen M, Lana SE, Ehrhart N, Fosmire SP, Thomas R, Jubala CM, Lamerato-Kozicki AR, Ehrhart EJ, Schaack J, Duke RC, Cutter GC, Bellgrau D. (2006) Naturally occurring translational models for development of cancer gene therapy. Gene Ther Mol Biol, 10, 31-40

Lamerato-Kozicki AR, Helm K, Jubala CM, Cutter GC, Modiano JF. (2006) Canine hemangiosarcoma originates from hematopoietic precursors with potential for endothelial differentiation. Exp Hematol, 34, 870-878

Khanna C, Lindblad-Toh K, Vail D, London C, Bergman P, Barber L, Breen M, Kitchell B, McNeil E, Modiano JF, Niemi S, Comstock K, Ostrtander E, Westmoreland S, Withrow S. (2006) Dogs, cancer, translation and genomics: a novel comparative opportunity. Nat Biotech, 24,1065-1066

Modiano JF, Breen M, Valli VEO, Wojcieszyn JW, Cutter GR. (2007) Predictive value of p16 or Rb inactivation in a model of naturally occurring canine non-Hodgkin lymphoma. Leukemia, 21, 184-187

Lin P-Y, Fosmire SP, Park S-H, Park J-Y, Baksh S, Modiano JF, Weiss RH. (2007) Attenuation of PTEN increases p21 stability in kidney cancer cells: potential mechanism of chemotherapy resistance. Mol Cancer, 6(1), 16

Fosmire SP, Thomas R, Jubala CM, Wojcieszyn J, Valli VEO, Getzy DM, Smith TL, Gardner LA, Ritt MG, Bell JS, Freeman KP, Greenfield BE, Lana SE, Kisseberth WC, Helfand SC, Cutter GR, Breen M, Modiano JF. (2007) Inactivation of the p16 cyclin-dependent kinase inhibitor in high-grade canine non-Hodgkin T-cell lymphoma. Vet Pathol, 44, 467-478

Complete list of Dr. Modiano's publications available through PubMed.

Updated: February 4, 2008