Abstract 5840: Normal fibroblasts, cancer-associated fibroblasts, and their senescent counterparts exert varying effects on tumorigenic potential and ABT-263 sensitivity of gastric cancer cells

Abstract It has become increasingly apparent that cancer is not a tumor cell-centric disease. Elements of the tumor microenvironment (TME), including fibroblasts and senescent cells, have been shown to contribute to tumor cell proliferation, metastasis, and therapy resistance, and are therefore major contributors to disease progression. However, this has been complicated by accumulating evidence suggesting that the function of fibroblasts is heterogeneous, with normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) both promoting or suppressing tumorigenesis and drug sensitivity within different contexts. Moreover, although senescent fibroblasts have been shown to accelerate tumor growth and contribute to therapy resistance, whether phenotypic differences exist between different senescent fibroblasts remains poorly understood. It is clear that additional work must be done to unravel the precise mechanisms by which NFs, CAFs, and their senescent counterparts interact within the tumor microenvironment to modulate tumor cell growth and sensitivity to therapy. Here, we show different NF and CAF lines exert varying effects on AGS gastric cancer cells. We found that when AGS cells are co-cultured with IMR90 lung fibroblasts, they form fewer and smaller colonies (total colony area = 5.14E3 pixels^2) than when cultured alone (total colony area = 2.57E4 pixels^2). On the other hand, colony formation ability is enhanced when AGS cells are co-cultured with GF1 primary gastric fibroblasts (total colony area = 3.56E4 pixels^2), and to a greater extent when cultured with CK4520 (total colony area = 4.59E4 pixels^2) and CK8612 (total colony area = 4.88E4 pixels^2) primary gastric CAFs. We next sought to determine whether these cells modulate AGS sensitivity to ABT-263, a BH3 mimetic that activates the intrinsic apoptotic pathway by targeting and inhibiting Bcl-2 and Bcl-xl. We treated AGS cells with ABT-263 with or without the addition of fibroblast-conditioned medium. We showed that IMR90 cells sensitize AGS cells to ABT-263, with an IC50 shift from 109 nM to 54 nM in AGS cells treated with IMR90-conditioned medium. On the other hand, AGS cells were more resistant to ABT-263 when treated with GF1, CK4520, or CK8612-conditioned medium, with IC50s of 270 nM, 520 nM, and 540 nM, respectively. Ongoing efforts involve expanding these experiments to senescent fibroblasts and conducting cytokine profiles to begin investigating the mechanisms underlying these phenotypes. These results contribute to our understanding of tumorigenesis and drug resistance. Citation Format: Francesca R. Di Cristofano, Shengliang Zhang, Kelsey E. Huntington, Wafik S. El-Deiry. Normal fibroblasts, cancer-associated fibroblasts, and their senescent counterparts exert varying effects on tumorigenic potential and ABT-263 sensitivity of gastric cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5840.