Molecular mechanisms driving mesenchymal colorectal cancer

驱动间充质结直肠癌的分子机制

基本信息

批准号：
10576886
负责人：
Jorge Moscat
金额：
$ 44.81万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-17 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576886
关键词：
ATAC-seq Address Adenocarcinoma Appearance Automobile Driving CD44 gene Cells Characteristics Clinic Collagen Colorectal Cancer Comprehension Data Desmoplastic Development Down-Regulation Epithelial Cells Epithelium Growth Human Hyaluronan Hyaluronidase Immunologic Surveillance Immunosuppression Impairment Incidence Intestinal Cancer Intestines Knockout Mice LGR5 gene Laboratories Ligands Link MAP Kinase Modules MAPK8 gene Mediating Mesenchymal Mitogen-Activated Protein Kinases Molecular Mus Mutation Neoplasms Organoids Pathway interactions Patients Phenotype Play Process Prognosis Property Publishing Receptor Cell Repression Role Sampling Series Signal Pathway Signal Transduction Testing Therapeutic Tissues Transcription Factor AP-1 Tumor Cell Invasion Tumor Suppressor Proteins Up-Regulation adenoma adverse outcome cancer cell colon cancer patients design immunosuppressed in vivo inhibitor innovation intestinal epithelium neoplastic cell new therapeutic target novel osteopontin prevent receptor stem stem cell biomarkers stem cells stemness transcription factor transcriptome sequencing tumor tumor initiation

项目摘要

SUMMARY A stem-mesenchymal phenotype of the tumor epithelium, and its associated immunosuppressive and desmoplastic stroma, are fundamental characteristics of the most aggressive and poor survival type of colorectal cancer CRC. However, the molecular and cellular mechanisms driving this process are still far from clear. This proposal stems from a series of recently published and unpublished observations in my laboratory that identify the two atypical PKCs (aPKC; PKC and PKC/) as novel tumor suppressors acting in concert to prevent this aggressive form of CRC. Thus, the simultaneous loss of both aPKCs in the intestinal epithelium (in a new DKOIEC mouse line) results in highly mesenchymal adenocarcinomas with a reactive and strongly immunosuppressed stroma. Both aPKCs are significantly downregulated in mesenchymal/stromal/ immunosuppressive CRC human patients who have the most unfavorable prognosis. Our unpublished preliminary data demonstrate that intestinal epithelial cells (IECs) deficient in PKC/ (or both aPKCs) upregulate the stem cell receptor CD44, concomitant with the downregulation of Lgr5+ intestinal stem cells, suggesting the appearance of a new type of tumor initiating cells (TICs). Inhibition of CD44+ in tumor organoids demonstrate its requirement for growth and supports its physiopathological relevance. Consistently, inhibition of one of the key CD44 stromal ligands (hyaluronan) in vivo abrogates the mesenchymal phenotype of DKOIEC tumors inhibiting the immunosuppressive response and restoring immunosurveillance. We hypothesize that the upregulation of a new type of CD44+/Lgr5- TICs by the loss of PKC/ is central in the development of the aggressive type of CRC. The upregulation of the MAP kinase cascades, together with the identification, in a series of unbiassed approaches, of the transcription factor KLF4 as a potential critical intermediary between PKC/ and CD44 expression, led us to hypothesize that the activation of ERK/JNK by PKC/ deficiency triggers AP1 and, concurrently, induces the degradation of KLF4; both actions cooperate to drive CD44 expression and the mesenchymal phenotype of very aggressive CRC. Therefore, in this proposal, we will determine the role of CD44 in the aggressive/mesenchymal type of CRC (Aim 1), as well as the molecular mechanisms whereby PKC/ regulates CD44 expression and function in this process (Aim 2). The successful completion of the proposed studies will create a new paradigm of significance and impact that will contribute to a more comprehensive understanding of the mechanisms driving the poor prognosis mesenchymal type of CRC, which will be key for the design of new therapeutic targets for this type of aggressive neoplasia.

概括肿瘤上皮的干间充质表型及其相关的免疫抑制和促纤维增生性基质，是最具攻击性和最差生存类型的基本特征然而，驱动这一过程的分子和细胞机制还很遥远。这个提议源于我实验室最近发表和未发表的一系列观察结果。鉴定出两种非典型 PKC（aPKC；PKC 和 PKC/）作为新型肿瘤抑制因子，协同作用因此，肠上皮中两种 aPKC 的同时丢失可以预防这种侵袭性的 CRC。一个新的 DKOIEC 小鼠系）导致高度间充质腺癌，具有反应性和强烈的免疫抑制的基质中，两种 aPKC 在间充质/基质/中均显着下调。我们未发表的免疫抑制性结直肠癌人类患者的预后最为不利。初步数据表明，肠上皮细胞 (IEC) 缺乏 PKC/（或两者 aPKC）上调干细胞受体 CD44，同时下调 Lgr5+ 肠道干细胞，表明肿瘤类器官中出现了一种新型肿瘤起始细胞 (TIC) 的 CD44+ 抑制作用。证明其对生长的要求并支持其病理生理学相关性。体内关键 CD44 基质配体（透明质酸）之一的缺失会消除 DKOIEC 的间充质表型肿瘤抑制免疫抑制反应并恢复免疫监视。 PKC/ 缺失导致新型 CD44+/Lgr5- TIC 的上调是 MAP 激酶级联的上调以及鉴定，是侵袭性类型的 CRC。一系列公正的方法，将转录因子 KLF4 作为潜在的关键中介 PKC/ 和 CD44 表达，使我们发现 PKC/ 缺陷对 ERK/JNK 的激活触发 AP1，同时诱导 KLF4 降解，这两种作用协同驱动 CD44；因此，在本提案中，我们将讨论非常侵袭性 CRC 的表达和间质表型。确定 CD44 在侵袭性/间质型 CRC 中的作用（目标 1），以及分子 PKC/ 在此过程中调节 CD44 表达和功能的机制（目标 2）。完成拟议的研究将创造一个具有重要意义和影响力的新范式，这将有助于更全面地了解导致不良预后间充质类型的机制 CRC，这将是设计此类侵袭性肿瘤新治疗靶点的关键。