Regulation of the tumor microenvironment by DNA damage repair proteins

DNA损伤修复蛋白调节肿瘤微环境

• 批准号: 10998271
• 负责人: Svasti Haricharan
• 金额: $ 18.51万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10998271
• 关键词: Regulation; tumor; microenvironment; DNA; damage

PROJECT SUMMARY Background ER+ breast cancer accounts for 2/3 of invasive breast cancer cases diagnosed in the world today. In patients, ~12% of ER+ tumors have complete loss of MLH1, a tumor suppressor and mismatch repair protein. We previously showed that MLH1 loss in ER+ breast cancer cells activates HER2 to induce resistance to standard endocrine therapy. However, the underlying mechanism remains unknown. Preliminary data support a role for MLH1 loss in altering secretion of HER ligands to mediate HER2 activation. This is of particular interest because an additional 14% of ER+ patient tumors have heterogeneous loss of MLH1. Although the functional consequence of heterogeneous MLH1 loss is as yet unknown, a role for MLH1 loss in altering the cancer secretome suggests a potentially significant impact on bulk tumor phenotypes. Hypothesis Based on our published work and preliminary data, the proposed study will test the hypothesis that MLH1 loss in ER+ breast cancer induces secretion of HER ligands, by co-opting cGAS-STING signaling, to promote HER2-dependent growth of both MLH1– and MLH1+ cells in heterogeneously MLH1– tumors. Specific Aims Aim 1 will test whether the secretion of HER ligands induced by MLH1 loss mediates HER2 activation to promote endocrine therapy resistance. Here, we will use both in vitro and in vivo approaches to determine whether the ligands secreted by MLH1- ER+ breast cancer cells promote HER2 heterodimerization and consequent activation, and thereby endocrine therapy resistant growth. Aim 2 will investigate the mechanism linking MLH1 loss to HER ligand secretion. Specifically, we will test whether inefficient DNA damage repair in the absence of MLH1 triggers the cGAS-STING secretory pathway. We will also determine how cGAS-STING activation promotes HER ligand secretion. Aim 3 will examine the therapeutic impact of heterogeneous MLH1 loss. Using in vitro and in vivo experimental models established in my lab, we will test whether HER2 activation in both MLH1+ and MLH1- cells in tumors with heterogeneous MLH1 loss renders these tumors globally susceptible to HER2 inhibitors. We will also use digital spatial profiling to assess the contribution of the secretome to signaling patterns and therapeutic response in heterogeneously MLH1- tumors. Impact The results of this study will present new therapeutic strategies to help >25,000 women diagnosed each year with ER+ breast cancer characterized by heterogeneous MLH1 loss. Our work will also provide novel insight into how MLH1 loss modulates the cGAS-STING pathway to promote a pro-growth tumor secretome. Overall, results from this study will shed new insight into the how MLH1 loss promotes cancer phenotypes.

项目摘要 背景ER+乳腺癌占当今世界诊断出的侵入性乳腺癌病例的2/3。在 患者约有12％的ER+肿瘤完全损失MLH1，肿瘤抑制剂和不匹配修复蛋白。 我们先前表明，ER+乳腺癌细胞中的MLH1丧失会激活HER2以诱导对标准的抗性 内分泌疗法。但是，基本机制仍然未知。初步数据支持 MLH1在改变配体的分泌物以介导HER2激活时损失。这是特别感兴趣的，因为 另外14％的ER+患者肿瘤具有MLH1的异质损失。虽然功能后果 异质MLH1损失的尚不清楚，MLH1损失在改变癌症的作用表明 对散装肿瘤表型的潜在显着影响。 假设基于我们发表的工作和初步数据，拟议的研究将检验以下假设。 ER+乳腺癌中的MLH1损失通过选择CGAS刺信信号传导诱导其配体的分泌 在异质MLH1-肿瘤中促进MLH1-和MLH1+细胞的HER2依赖性生长。 特定目标目标1将测试MLH1损失介导的配体的分泌是否 激活以促进内分泌疗法抗性。在这里，我们将同时使用体外和体内方法 确定MLH1-ER+乳腺癌细胞分泌的配体是否促进HER2异二聚化 并因此激活，从而抗内分泌疗法的生长。 AIM 2将研究机制 将MLH1损失与配体分泌联系起来。具体而言，我们将测试是否效率低下的DNA损伤修复 MLH1的缺失触发了CGAS-Sting Secret Pathway。我们还将确定CGAS键 激活促进了她的配体分泌。 AIM 3将检查异质MLH1的治疗影响 损失。使用我实验室中建立的体外和体内实验模型，我们将测试HER2激活是否激活 在具有异质MLH1损失的肿瘤中的MLH1+和MLH1细胞中，这些肿瘤在全球范围内使这些肿瘤呈现 容易受到HER2抑制剂的影响。我们还将使用数字空间分析来评估秘密的贡献 在异质MLH1肿瘤中的信号传导模式和治疗反应。 影响这项研究的结果将提出新的治疗策略，以帮助> 25,000名被诊断的妇女 ER+乳腺癌的一年，其特征是异质MLH1损失。我们的工作还将提供新颖的见解 MLH1损失如何调节CGAS刺途径以促进促肿瘤的肿瘤分泌组。全面的， 这项研究的结果将对MLH1损失如何促进癌症表型的新见解。