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.

项目摘要 细胞衰老是肿瘤抑制的细胞生长停滞，由诱导剂（例如护理）触发 上皮卵巢癌（EOC）化学治疗铂，称为治疗诱导的衰老。 但是，衰老细胞是可行的，可能会促进治疗复发和免疫逃脱 细胞因子，趋化因子和生长因子等因素的分泌称为衰老 相关的分泌表型（SASP）。因此，选择性消除有害的理想 SASP在保持衰老相关的生长停滞的同时。发展新颖的治疗性 克服抗治疗的策略仍然是克服EOC的主要障碍。因此， 该提案的总体目标是调查SASP的基础机制并利用这些机制 新获得的机械见解以开发基于衰老的组合EOC治疗剂。 CGA 通过识别衰老过程中的细胞质染色质片段（CCF）来促进SASP。我们的 初步研究表明，蛋白质硫氧还蛋白还原酶1（TXNRD1）局部与CCF和 TXNRD1抑制会损害CGA在CCF，CGAS-Sting途径和SASP中的定位 在铂诱导的E​​OC衰老期间。值得注意的是，TXNRD1抑制不影响衰老 相关的生长停滞。本应用程序的目标是调查信号基础 TXNRD1控制SASP并研究基于衰老的EOC治疗 战略。我们的中心假设是TXNRD1通过 SASP通过在治疗引起的EOC衰老期间激活CGAS刺信信号传导途径。 因此，提出了两个具体目标：目标1是阐明分子机制 TXNRD1调节衰老过程中的SASP，AIM 2将确定TXNRD1在EOC中的作用 治疗反应。拟议的研究是高度新颖的，因为这是第一个探索一个的研究 通过CCF调节CGAS插入信号通路来控制SASP的分子开关。因此， 我们的研究是阐明SASP调节分子基础的潜力的范式转移 在衰老期间。提出的研究具有很高的影响，因为它将为 最终通过限制与SASP相关的治疗，制定急性新颖的EOC治疗策略 复发和抵抗。因此，当前的研究不仅将提供关键的机理见解 SASP在衰老过程中的调节，但也将对发展具有深远的影响 基于衰老的治疗策略。