Abstract 1345: p21 (WAF1/CIP1) drives a secretory phenotype in senescent fibroblasts and promotes bystander cancer cell growth in the tumor microenvironment

Abstract

Abstract Cancer associated fibroblasts (CAF) are major stromal cells in the tumor microenvironment (TME) and support cancer cell growth. Chemotherapy can induce CAF senescence in which p21 (the cyclin-dependent kinase inhibitor) permanently arrests the cell cycle. Cellular senescence and its associated secretory phenotype (SASP) can promote cancer progression and lead to drug resistance. We explored molecular mechanisms of p21 in the cellular communication between cancer and senescent fibroblasts. We induced fibroblast cell senescence by treatment with etoposide. Cellular senescence was confirmed by cytokine profiling, beta-gal staining and high p21 expression. To evaluate the role of p21 in the SASP of senescent fibroblasts, we transiently knocked down p21 expression in senescent fibroblast cells using siRNA. SA-beta-gal staining showed a strong beta-gal expression around nuclei in the senescent fibroblast cells with the knockdown of p21, which is the same as it was in the cells with siRNA control. Further cytokine profiling showed two panels of SASP upon p21 knockdown in senescent cells: 1) decrease of cytokines such as CCL2 and IL8 and 2) increase of cytokines such TNF-alpha correlated to the knockdown of p21 in the senescent cells. These results suggest that p21 drives a SASP in senescent fibroblast cells, in addition to its function in cell cycle arrest. We examined the effect of the p21-driven SASP in senescent fibroblasts on bystander cancer cell growth in the TME. Our co-culture system showed knockdown of p21 in senescent fibroblasts suppressed bystander cancer cell growth. We found that knockdown of TNF partially blocked the antiproliferation effect of p21-knockdown on bystander cancer cells. Our results suggest that senescent fibroblasts support bystander cancer cell growth via a p21-driven SASP in the TME and provides a new strategy for targeting p21-driven SASP in the TME for cancer therapy. Citation Format: Shengliang Zhang, Kelsey E. Huntington, Lanlan Zhou, Wafik S. El-Deiry. p21 (WAF1/CIP1) drives a secretory phenotype in senescent fibroblasts and promotes bystander cancer cell growth in the tumor microenvironment [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 1345.