Signaling basis of senescence-associated secretory phenotype and its implications in epithelial ovarian cancer

Project Summary Cellular senescence is a tumor-suppressive cell growth arrest triggered by inducers such as stand-of-care epithelial ovarian cancer (EOC) chemotherapeutic platinum, known as therapy-induced senescence. However, senescent cells are viable and may promote therapy relapse and immune escape through the

secretion of factors such as cytokines, chemokines, and growth factors, termed the senescence- associated secretory phenotype (SASP). Thus, it would be ideal to selectively eliminate the detrimental SASP while maintaining the senescence-associated growth arrest. Developing novel therapeutic strategies to overcome therapy resistance remains a major obstacle to overcome in combating EOC. Thus,

the overall goal of this proposal is to investigate the mechanism underlying the SASP and leverage these newly gained mechanistic insights to develop senescence based combinatory EOC therapeutics. cGAS promotes the SASP through recognizing cytoplasmic chromatin fragments (CCF) during senescence. Our

preliminary studies show that the protein Thioredoxin Reductase 1 (TXNRD1) is localized to CCF and TXNRD1 inhibition impairs the localization of cGAS into CCF, the cGAS-STING pathway, and the SASP during platinum-induced senescence in EOC. Notably, TXNRD1 inhibition does not affect senescence- associated growth arrest. The objectives of this application are to investigate the signaling basis by which

TXNRD1 controls the SASP and to investigate a combination senescence based EOC therapeutic strategy. Our central hypothesis is that TXNRD1 promotes therapy relapse and resistance through the SASP by activating the cGAS-STING signaling pathway during therapy-induced senescence in EOC. Accordingly, two specific aims are proposed: Aim 1 is to elucidate the molecular mechanism by which

TXNRD1 regulates the SASP during senescence, and Aim 2 will determine the role of TXNRD1 in EOC therapy response. The proposed studies are highly novel because this is the first study to explore a molecular switch that controls the SASP by regulating the cGAS-STING signaling pathway via CCF. Thus, our studies are paradigm-shifting in their potential to elucidate the molecular basis of SASP regulation

during senescence. The research proposed is of high impact because it will lay the critical foundation for ultimately developing urgently novel EOC therapeutic strategies through limiting SASP-associated therapy relapse and resistance. Therefore, the current study will not only provide critical mechanistic insights into

SASP regulation during senescence but will also have far-reaching implications for the development of senescence-based therapeutic strategies.