Abstract 124: The soluble factor SPINK1 is a biomarker of therapeutically damaged TME that confers acquired resistance and an exploitable molecular target in human cancer medicine
Authors: Sun Yu 
Published: August 2018

Clinical efficacy of most anticancer treatments is frequently compromised by the development of cancer resistance arising as either a consequence of innate adaptation of cancer cells, or acquired fitness conferred by extracellular factors generated by the surrounding tumor microenvironment (TME). Of note, stromal cells in the TME become overtly senescent upon genotoxic treatment and develop a senescence-associated secretory phenotype (SASP), the latter characterized by secretion of numerous soluble factors that are responsible for disease exacerbation. We recently disclosed significant upregulation of the serine protease inhibitor Kazal type I (SPINK1) in human prostate stroma after chemotherapy of prostate cancer (PCa) patients. SPINK1, originally reported as a pancreatic secretory trypsin inhibitor, prevents pancreatic tissues from protease degradation with expression normally restricted to gastrointestinal (GI) tract organs. However, the influence of SPINK1 as a TME-derived soluble factor on cancer progression remains unexplored. In this study, we defined the expression modality and biological roles of SPINK1 in a therapy-damaged and functionally activated TME under therapeutic pressure. Distinct from a recent finding that revealed the involvement of a regulatory circuit comprising HNF4G and HNF1A in the PCa-GI transcriptome, we found that SPINK1 expression in human stromal cells is regulated by alternative transcriptional factors including NF-κB and C/EBP in response to chemotherapy. TME-released SPINK1 can significantly enhance the aggressiveness of PCa cells including accelerated proliferation, increased migration, elevated invasion and more importantly, enhanced chemoresistance. SPINK1 triggers a typical epithelial-mesenchymal transition in cancer cells, a process mediated by EGFR/PI3K/Akt and MAPK/Erk signaling. Further, SPINK1 remarkably reprograms PCa cells by inducing a cancer stem cell (CSC)-like phenotype and promoting transdifferentiation of cancer cells toward neovasculature. As supporting evidence, our preclinical 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. Thus, our study demonstrates that SPINK1 is a soluble biomarker of therapeutically damaged TME and represents a potentially exploitable molecular target in human cancer clinics.

Citation Format: Yu Sun. The soluble factor SPINK1 is a biomarker of therapeutically damaged TME that confers acquired resistance and an exploitable molecular target in human cancer medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 124.