Cell type and molecular determinants of colorectal cancer initiation downstream of APC inactivation

APC 失活下游结直肠癌发生的细胞类型和分子决定因素

• 批准号: 10224130
• 负责人: Ning Li
• 金额: $ 8.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-19 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224130
• 关键词: APC gene; Address; Automobile Driving; Award; Cancer Etiology; Cell Cycle; Cells; Cessation of life; Colorectal Cancer; Data; Event; Family; Genetic Techniques; Genomics; Goals; Growth; Intestines; Maintenance; Malignant Neoplasms; Metabolic Activation; Molecular; Mutate; Oncogenic; Pathway interactions; Publishing; RNA-Binding Proteins; Refractory; Research; Specificity; Testing; Therapeutic Intervention; Tumor Suppressor Proteins; WNT Signaling Pathway; Work; cancer initiation; cell type; gain of function; intestinal epithelium; novel; stem cell population; stem cells; tumorigenesis

Project Summary Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally. The long-term objective of my research on this award will be to understand the cell-type specificity and molecular mechanisms through which inactivation of the APC tumor suppressor drives the ontogeny of colorectal cancer. APC is mutated in the vast majority of CRC and is broadly considered the initiating event in most of these cancers. Because of this, there has been a large amount of research into the molecular mechanisms through which APC functions. APC is a well-established negative regulator of the canonical Wnt signaling pathway, and consequently a wealth of evidence exists demonstrating that constitutive Wnt pathway activation downstream of APC loss is necessary for initiation and maintenance of CRC. Recent data however suggests that this body of research has largely overlooked several additional important functions of this tumor suppressor, and that such functions will represent valuable points for preventative action and therapeutic intervention in CRC. Specifically, I have uncovered additional oncogenic pathways activated upon APC loss that are also necessary for initiation and maintenance of CRC. In particular, I recently published data demonstrating that the Msi family of RNA binding proteins are activated upon APC loss in a pathway that appears to lie in parallel to and not downstream of -CATENIN. I went on to show that Msi activity is necessary for CRC initiation and maintenance, and that Msi gain of function alone is sufficient to transform the intestinal epithelium in a Wnt-independent manner. At the cellular level, my colleagues and I found that Msi activity acts specifically to drive metabolic activation of quiescent (in G0) intestinal stem cells (ISCs) resulting in cell cycle entry, proliferation, and a block in their differentiation. In contrast, Msi activity has no discernable molecular effect on the active ISC population driven by Wnt pathway activity and previously posited to be the cell-of-origin in CRC. Previous studies have found that these quiescent ISCs are refractory to canonical Wnt pathway stimulation in their dormant state. Therefore, the central hypothesis of my work in the Lengner lab moving forward is that loss of APC can initiate tumorigenesis through promiscuous activation of quiescent intestinal stem cells via Wnt-independent mechanisms. I propose that APC loss initiates a number of oncogenic pathways independent of the canonical Wnt pathway activation (including Msi induction). I will test whether APC loss can initiate CRC by driving quiescent ISCs out of G0 and into the cell cycle, thus establishing quiescent ISCs as a cell-or-origin in colorectal cancer. I will address this hypothesis using a combination of genomic and genetic techniques with the ultimate goal of testing whether Wnt- independent pathways activated downstream of APC loss are viable points for therapeutic intervention in CRC.

项目摘要 结直肠癌(CRC)是全球癌症相关死亡的主要原因。的长期目标是 我对这个奖项的研究将是为了了解细胞类型的特异性和分子机制 APC抑癌基因的失活通过该机制驱动结直肠癌的个体发生。装甲运兵车 在绝大多数CRC中发生突变，并被广泛认为是大多数 癌症。正因为如此，人们对分子机制进行了大量的研究。 APC通过它发挥作用。APC是规范WNT的一个公认的负调节因子 信号通路，因此存在大量证据表明，构成Wnt APC缺失下游通路的激活对于CRC的启动和维持是必要的。近期 然而，数据表明，这一研究机构在很大程度上忽略了几个额外的重要因素 这种肿瘤抑制因子的功能，以及这些功能将是预防的有价值的要点 结直肠癌的行为和治疗干预。具体地说，我发现了更多的致癌途径 在APC丢失时激活，这也是启动和维护CRC所必需的。尤其是，我 最近公布的数据表明，MSI RNA结合蛋白家族在 在一条似乎与-连环蛋白平行而非下游的途径中，蛋白原结合蛋白丢失。我继续做了 表明MSI活动对于CRC启动和维护是必要，且MSI获得了功能 仅此一项就足以以不依赖于Wnt的方式转化肠道上皮。在手机上 水平，我和我的同事们发现MSI活性专门作用于推动新陈代谢激活 静止的(在G0中)肠道干细胞(ISCs)导致细胞周期进入、增殖和阻止其 差异化。相反，MSI活性对活跃的ISC群体没有明显的分子效应 由Wnt途径活性驱动，以前被认为是结直肠癌的起源细胞。以前的研究 已经发现，这些静止的ISCs对规范的Wnt途径刺激在其 休眠状态。因此，我在伦格纳实验室工作的中心假设是 APC的缺失可通过静止肠道的混乱激活而启动肿瘤的发生 干细胞通过不依赖于Wnt的机制。我建议APC的损失会引发一些 致癌途径不依赖于典型的Wnt途径激活(包括MSI诱导)。这就做 测试APC丢失是否会通过将静止的ISCs赶出G0并进入细胞周期来启动CRC，因此 建立静止的ISCs作为结直肠癌的细胞或来源。我将使用一个 基因组和基因技术的结合，最终目标是测试Wnt- APC丢失下游激活的独立通路是进行治疗干预的可行点 CRC。