ABSTRACT Therapeutic approaches aimed at curing prostate cancer (PrCa) are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to chemical castration of PrCa patients. Recently, we have, for the first time, described αvβ6, a surface receptor of the integrin family as a novel therapeutic target for PrCa treatment; this molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We have demonstrated unique properties of this molecule in PrCa that are not observed for other integrins: we have shown that αvβ6 promotes castrate- resistant prostate cancer (CRPC) via activation of JNK and androgen receptor (AR). Furthermore, we have shown that αvβ6 is found in cancer cell exosomes, is transferred from cancer cells to recipient cells by exosomes and remains active in the recipient cells. We also demonstrate that αvβ6 has profound effects on the microenvironment. Specifically, αvβ6 prevents induction of the Stat1/Mx1/2 signaling pathway in donor cancer cells, and their exosomes, and its down-regulation in cancer cell exosomes inhibits monocyte M2 polarization. Finally, we demonstrate that αvβ6 inhibition in vivo causes upregulation of the Stat1/MxA/B signaling pathway in cancer cells. Based on our highly rigorous mechanistic studies, we propose the following innovative hypothesis: αvβ6 expression affects the microenvironment by down-regulating Stat1/Mx1 levels in donor cells, and subsequently in cancer cell exosomes and recipient cells, thereby promoting monocyte differentiation, tumor growth, and cancer progression. Consequently, by down-regulating or inhibiting αvβ6 in cancer cells, increased Stat1/MxA/B levels in cells/ exosomes/ monocytes will be generated producing an anti-tumor effect. To test this hypothesis, we plan the following three specific aims. We will examine in vitro the role of αvβ6 integrin in regulating cancer cell - monocyte crosstalk (Aim 1), and analyze in vivo the functional role of the pathway mediated by exosomal αvβ6 and/or Stat1 in cancer progression (Aim 2) and characterize the αvβ6 integrin/Stat1 pathway in PrCa cells (Aim 3). Innovative approaches, highly purified exosomes and in vivo models will be used to test our hypothesis that transfer of integrins and their downstream effectors from cancer cells to other cells in the tumor microenvironment promotes CRPC. The study will be supported by a multidisciplinary team of investigators who have extensive and complementary expertise in all the required technologies. Based on our preliminary data on the αvβ6/Stat1 pathway and planned experimental design for this project, we expect that our study will elucidate new mechanisms that promote PrCa and validate new targets for PrCa therapeutic approaches.