The role of the senescent microenvironment on cancer initiating cells in the colon.

衰老微环境对结肠癌起始细胞的作用。

• 批准号: 10638374
• 负责人: William Mallory Grady
• 金额: $ 6.94万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638374
• 关键词: role; senescent; microenvironment; cancer; initiating

PROJECT SUMMARY/ABSTRACT Advanced age is the single most significant risk factor for cancer. Although there are many plausible age-related mechanisms that mediate the increased risk for cancer in the elderly, functional evidence is lacking for the majority of these mechanisms. This proposal will focus on the role of the aged microenvironment, particularly senescence, in promoting the formation of colorectal cancer (CRC), which is a common age-related cancer in the U.S. It is well established that the majority of CRCs arise through the serial accumulation of mutations and epigenetic alterations in oncogenes and tumor suppressor genes in colon epithelial stem cells. However, our group and others have found cells with cancer-causing DNA alterations (e.g. oncogenic KRAS and TP53) in the histologically normal colon mucosa of people, which suggests that the DNA alterations alone are not sufficient to drive the complete CRC formation process. Our group has recently shown that a senescent normal colon tissue microenvironment can promote the neoplastic behavior of colon epithelial cells ex vivo. We found increased senescent fibroblasts in the colons of the elderly and of people at high risk for CRC. We found that certain senescence associated secretory phenotype (SASP) factors produced by senescent fibroblasts can induce cancer hallmark behaviors through the activation of oncogenic signaling pathways. Based on our preliminary data we hypothesize that senescent fibroblasts in older people and the accompanying specific Senescence Associated Secretory Phenotype (SASP) secreted proteins promote the tumorigenesis of colon epithelial cells that have acquired age-related oncogenic mutations, which we have defined as cancer-initiating cells. To provide direct functional evidence to test this hypothesis, we propose the following Specific Aims: AIM 1A. To determine whether senescent fibroblasts can promote the survival and/or transformation of colon cancer initiating cells in ex vivo and in vivo organoid model systems. AIM 1B. To determine the necessary and sufficient role of specific cancer-associated SASP factors produced by the senescent fibroblasts in cancer formation. AIM 2. To determine whether a senescent tissue microenvironment is necessary for the survival and clonal expansion of mutant APC and mutant KRAS cancer-initiating cells using a well characterized CRC mouse model, the inducible Villin-Cre;Apcflx/flx; KrasLSL-G12D (AK) mice, with two approaches: AIM 2A: a pharmacological approach using the senomorphic drug rapamycin and the senolytic drug treatment DNQ (dasatinib and quercetin) AIM 2B: a genetic approach using the p16-3MR transgenic model, which allows the inducible ablation of senescent cells.

项目摘要/摘要 高龄是癌症的唯一最重要的危险因素。虽然有很多 合理的与年龄相关的机制，介导了老年人的癌症风险增加， 这些机制中的大多数缺乏功能证据。该提议将重点放在 老化的微环境，尤其是衰老的作用在促进形成 结直肠癌（CRC），这是美国常见的年龄相关癌症 大多数CRC是通过突变和表观遗传的序列积累而产生的 结肠上皮干细胞中的癌基因和肿瘤抑制基因的改变。然而， 我们的小组和其他人发现了引起癌症的DNA改变的细胞（例如致癌KRAS 和TP53）在人的组织学正常结肠粘膜中，这表明DNA 仅改动就不足以驱动完整的CRC形成过程。 我们的小组最近表明，衰老的正常结肠组织微环境可以 促进结肠上皮细胞离体的肿瘤行为。我们发现衰老增加 老年人的成纤维细胞和CRC高风险的人的成纤维细胞。我们发现确定 衰老相关分泌表型（SASP）因衰老成纤维细胞产生的因子 可以通过激活致癌信号通路来诱导癌症标志行为。 根据我们的初步数据，我们假设老年人和 伴随的特定衰老相关分泌表型（SASP）分泌蛋白 促进已经获得与年龄相关的致癌性的结肠上皮细胞的肿瘤发生 突变，我们将其定义为癌症引发细胞。提供直接的功能证据 为了检验这一假设，我们提出了以下特定目的： 目标1a。确定衰老成纤维细胞是否可以促进生存和/或 结肠癌的转化在体内和体内器官模型系统中引发细胞。 目标1B。确定特定癌症相关SASP的必要和足够作用 衰老成纤维细胞在癌症形成中产生的因素。 目标2。确定衰老组织微环境是否需要生存 以及使用井 表征CRC小鼠模型，可诱导的villin-cre; apcflx/flx; Kraslsl-G12D（AK）小鼠，有两只 方法：AIM 2A：一种使用鼻型药物雷帕霉素和 鼻溶剂治疗DNQ（dasatinib和槲皮素）AIM 2B：一种使用的遗传方法 P16-3MR转基因模型，允许诱导的衰老细胞诱导。