Abstract A15: Interaction between cancer-associated fibroblasts and apoptotic cancer cells inhibits the migration and invasion of lung cancer cells and cancer-associated fibroblasts preventing the development of metastasis

Abstract

Abstract The interplay between apoptotic cancer cells and the tumor microenvironment (TME) modulates cancer progression and metastasis. Cancer-associated fibroblasts (CAFs) play a crucial role in promoting these events through paracrine communication. In the present study, we investigated how the interaction of CAFs with apoptotic lung cancer cells modulates migration and invasion of cancer cells and CAFs. CAFs isolated from the lung tumors of Kras-mutant (KrasLA1) mice and ultraviolet-irradiated apoptotic cancer cells, including 344SQ (murine), A549 and HCT116 cells (human), were used for Transwell migration and invasion assays. Western blotting, real-time quantitative PCR, immunofluorescence staining, cytokine array, ELISA, and flow cytometry were used to assess TGFβ1 signaling pathways, CAF activation markers, Notch1 signaling pathways and phagocytosis. For in vivo study, apoptotic 344SQ cells with or without the Notch1 inhibitor LY3039478 were injected following subcutaneously injection of 344SQ cells into syngeneic (129/Sv) mice. In addition, conditioned medium (CM) derived from CAFs with or without neutralizing mouse anti-WISP-1 antibody or isotype IgG was administered via intratumoral injection. Interaction of lung CAFs and apoptotic cancer cells suppressed TGFb1-induced migration and invasion of cancer cells and CAFs. Enhanced secretion of Wnt-induced signaling protein 1 (WISP-1) by CAFs exposed to apoptotic 344SQ cells (ApoSQ) was required for these anti-migration and -invasion effects. Pharmacologic inhibition of Notch1 activation or siRNA-mediated Notch1 silencing prevented WISP-1 production by CAFs and reversed the anti-migration and -invasion effects. In addition, a single injection of ApoSQ enhanced WISP-1 production, suppressed expression of CAF activation markers in isolated Thy1+ CAFs, and inhibited lung metastasis in syngeneic immunocompetent mice via Notch1 signaling. Treatment with ApoSQ-exposed CAF CM suppressed lung metastasis, whereas WISP-1-immunodepleted ApoSQ-exposed CAF CM reversed the anti-metastatic effect. Citation Format: Hee Ja Kim, Kyungwon Yang, Kiyoon Kim, Jihee Lee Kang. Interaction between cancer-associated fibroblasts and apoptotic cancer cells inhibits the migration and invasion of lung cancer cells and cancer-associated fibroblasts preventing the development of metastasis [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A15.