Studies carried out by our laboratory during the current funding cycle, reached important milestones in the characterization of b1 integrins as novel regulators of intracellular signaling pathways participating in tumor progression in vivo. Using molecular and genetically engineered models of prostate cancer, we have now established a central role for b1 integrins in orchestrating cross-talk signaling with growth factor receptors, mostly the insulin-like growth factor receptor-1 (IGF-IR), modulating the activation of cytoplasmic kinases, including AKT and Focal Adhesion Kinase (FAK), and promoting tumor cell survival by counteracting apoptosis. We found that these responses are prominently exploited in prostate cancer progression, where b1 integrin-directed signaling is required for primary tumor growth, promotes metastatic dissemination, and antagonizes tumor response to therapy, especially ionizing radiation. Therefore, we formulated a unifying hypothesis that b1 integrins orchestrate multiple intracellular signaling pathways of gene expression, cell motility and cell survival in prostate cancer progression and this will constitute the focus of the present application for the next funding cycle. Experiments in specific aim 1 will dissect the role of b1 integrins in vitro and in vivo in the control of the sonic hedgehog pathway in tumor cells. The pro-metastatic functions of b1 integrins through a novel pathway of tumor cell migration and metastasis will be investigated in the second specific aim, with emphasis on dynamic redistribution of b1 integrins by Trop-2, a transmembrane receptor that is up-regulated in prostate cancer, in specialized subcellular microdomains of prostate cancer cells. The third specific aim will characterize a novel cell survival mechanism mediated by b1 integrins in prostate cancer cells, and centered on their selective inhibition of JNK1-mediated apoptosis in response to ionizing radiation. Overall, the application combines detailed elucidation of mechanistic pathways in vitro, with validation studies using state-of-the-art molecular and genetic models of prostate cancer in vivo. The results will uncover novel aspects of b1 integrin signaling important for cancer progression, and will establish a mechanistic foundation for novel translational approaches in prostate cancer therapy.

Public Health Relevance

The present study will elucidate a novel molecular network of synergistic cooperation between surface receptors and their downstream targets, and it will provide new insights in the current therapeutic approaches for prostate cancer that target either integrins or the insulin-like growth factor receptor. This line of investigations will establish a broad mechanistic foundation for novel translational approaches in the treatment of advanced and metastatic prostate cancer. Overall, the application combines multidisciplinary state-of-the-art approaches from several fields of investigation into a single, integrated experimental platform, uniquely positioned to unravel novel pathogenetic mechanisms of prostate cancer progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109874-09
Application #
8616721
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2004-09-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
9
Fiscal Year
2014
Total Cost
$235,111
Indirect Cost
$83,426
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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Singh, Amrita; Fedele, Carmine; Lu, Huimin et al. (2016) Exosome-mediated Transfer of αvβ3 Integrin from Tumorigenic to Nontumorigenic Cells Promotes a Migratory Phenotype. Mol Cancer Res 14:1136-1146
Fedele, Carmine; Singh, Amrita; Zerlanko, Brad J et al. (2015) The αvβ6 integrin is transferred intercellularly via exosomes. J Biol Chem 290:4545-51
Trerotola, Marco; Ganguly, Kirat K; Fazli, Ladan et al. (2015) Trop-2 is up-regulated in invasive prostate cancer and displaces FAK from focal contacts. Oncotarget 6:14318-28
Dutta, Anindita; Li, Jing; Fedele, Carmine et al. (2015) αvβ6 integrin is required for TGFβ1-mediated matrix metalloproteinase2 expression. Biochem J 466:525-36
Trerotola, Marco; Jernigan, Danielle L; Liu, Qin et al. (2013) Trop-2 promotes prostate cancer metastasis by modulating ýý(1) integrin functions. Cancer Res 73:3155-67
Goel, Hira Lal; Sayeed, Aejaz; Breen, Michael et al. (2013) ýý1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase 1. J Cell Physiol 228:1601-9
Sayeed, Aejaz; Fedele, Carmine; Trerotola, Marco et al. (2013) IGF-IR promotes prostate cancer growth by stabilizing α5β1 integrin protein levels. PLoS One 8:e76513
Trerotola, Marco; Li, Jing; Alberti, Saverio et al. (2012) Trop-2 inhibits prostate cancer cell adhesion to fibronectin through the β1 integrin-RACK1 axis. J Cell Physiol 227:3670-7
Altieri, Dario C; Stein, Gary S; Lian, Jane B et al. (2012) TRAP-1, the mitochondrial Hsp90. Biochim Biophys Acta 1823:767-73

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