Abstract 2972: SPINK1, a soluble factor released by the therapy-damaged tumor microenvironment, promotes prostate cancer resistance

Abstract

Abstract Cancer evolution is driven by not only the genetic and/or epigenetic alterations of cancer cells, but also diverse factors that are derived from the surrounding tumor microenvironment (TME). Upon chemotherapy or radiation, stromal cells in the TME become senescent and develop a senescence-associated secretory phenotype (SASP) that is characterized by secretion of a large number of cytokines, chemokines, growth factors, and proteases. In most cases, the SASP is functionally regulated by the DNA damage secretory program (DDSP) and pathophysiologically responsible in vivo for disease exacerbation. We recently disclosed significant upregulation of the serine protease inhibitor Kazal type I (SPINK1) in primary normal human prostate fibroblasts after exposure to DNA damaging agents. SPINK1 plays critical roles in cancer cell proliferation, survival and motility in multiple human malignancies, but its influence as a soluble TME-associated factor on cancer progression remains unknown. In this study, we performed a series of molecular and cellular studies to define the biological roles of SPINK1 in an activated TME. Promoter analysis indicated that SPINK1 expression in the fibroblasts is regulated by multiple transcriptional factors including the NF-κB complex in response to genotoxic stress. Fibroblast-derived SPINK1 can significantly enhance the aggressiveness of prostate cancer cells including accelerated proliferation, increased migration, elevated invasion and more importantly, enhanced chemoresistance. SPINK1 triggers a typical epithelial-mesenchymal transition (EMT) in cancer cells, a process mediated by EGFR/PI3K/Akt and MAPK/Erk signaling pathways. Consistent with the in vitro data, our in vivo studies suggested that SPINK1 expression in the prostate TME substantially promoted cancer survival and disease progression. Clinical investigation revealed increased expression of SPINK1 in the stroma of multiple organ types including the prostate, lung and breast of cancer patients after chemotherapy, implying the systemic induction of SPINK1 by anticancer agents. Overall, our study demonstrates that SPINK1 is a soluble biomarker of therapeutically damaged TME and represents a potentially exploitable molecular target in human prostate cancer clinics. Note: This abstract was not presented at the meeting. Citation Format: Fei Chen, Da Fu, Eric Lam, Yu Sun. SPINK1, a soluble factor released by the therapy-damaged tumor microenvironment, promotes prostate cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2972. doi:10.1158/1538-7445.AM2017-2972