Abstract 6137: Tumor-derived endothelin-1 recruits and activates fibroblasts to support tumor aggressiveness

Abstract

Abstract The recruitment of fibroblasts to tumor and their activation to cancer-associated fibroblast (CAF) is an exploited strategy used by tumor to guide matrix remodeling, supporting cancer invasion and metastatic disease. CAFs are the major effectors of extracellular matrix (ECM) remodelling through secretion of collagens, cross-linking enzymes and proteases, and in turn engagement of integrins. Although several tumor cell-secreted factors have been identified in generating tumor-promoting stroma, there has been a great interest to define factors and associated molecular mechanisms involved in promoting CAF premetastatic function. Tumor-related endothelin-1 (ET-1) has an important role in the crosstalk between cancer and stromal cells supporting serous ovarian cancer (SOC) progression. By binding its receptors (ETAR and ETBR), ET-1 favours the recruitment of the protein β-arrestin-1 and the generation of signaling complexes regulating also cytoskeleton reorganization, thereby fine-tuning SOC cell invasion and metastasis. However, how the integration of ET-1 receptors might “educate” stroma to become permissive for invasion, supplying an altered ECM governing metastasis needs to be investigated. In this study, we identified endothelin-1 as a key factor in priming CAF conversion in SOC. We demonstrate that primary ovarian fibroblasts express ETA and ETB, along with β-arrestin1, and secrete ET-1; b) the autocrine and cancer-secreted ET-1 promotes fibroblast proliferation, and an increase in the expression of CAF markers (αSMA, vimentin and FAP), secretion of proinflammatory cytokines, collagen contraction ability and cell motility. Moreover, ET-1 induces activation of b1 integrin and downstream signaling. Mechanistically, ET1R/intb1 signaling allows ECM remodeling, either by promoting and invasive protrusion formation, invadosome, and collagen secretion. Importantly, therapeutical inhibition of ET-1 receptors with Ambrisentan and intβ1 with ATN-116 markedly reduced the ability of SOC cells to adhere in the intraperitoneal organs and to metastasize. Our findings support a model in which ET-1 educates the stromal fibroblasts to become permissive for tumor invasion and demonstrate for the time the significance of an ET-1-dependent integrin signaling in this process. Citation Format: Danila Del Rio, Valentina Caprara, Ilenia Masi, Francesca Spadaro, Sara Giannitelli, Alberto Rainer, Anna Bagnato, Laura Rosanò. Tumor-derived endothelin-1 recruits and activates fibroblasts to support tumor aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6137.