Molecular mechanisms driving mesenchymal colorectal cancer

驱动间充质结直肠癌的分子机制

• 批准号: 10374108
• 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
• 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/10374108
• 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; Epithelial Cells; Growth; Human; Hyaluronan; Hyaluronidase; Immunologic Surveillance; 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; Sum; 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; response; stem; stem cell biomarkers; stem cells; stemness; transcription factor; transcriptome sequencing; tumor

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 This proposal stems from a series of recently published and unpublished observations in my laboratory that identify the two atypical PKCs (aPKC; PKC and PKC/) as novel tumor suppressors acting in concert to prevent this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 Our unpublished preliminary data demonstrate that intestinal epithelial cells (IECs) deficient in PKC/ (or both aPKCs) upregulate the stem cell receptor CD44, concomitant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.

摘要 肿瘤上皮的干细胞-间充质表型及其相关的免疫抑制和 促结缔组织间质，是最具侵袭性和较差存活率类型的基本特征 结直肠癌，结直肠癌。然而，推动这一过程的分子和细胞机制仍远未 安全。这一建议源于我实验室最近发表和未发表的一系列观察结果。 确定两个非典型的PKC(aPKC；PKC和PKC/)是协同作用的新的肿瘤抑制因子 防止这种侵略性形式的CRC。因此，肠上皮中两个蛋白激酶C的同时丢失(在 一种新的DKOIEC小鼠品系)导致高度间叶性腺癌，其反应性和强 免疫抑制的间质。两种APKC在间质/间质中的表达均显著下调 免疫抑制的结直肠癌患者预后最差。我们未出版的 初步数据显示，肠上皮细胞(IECs)缺乏PKC/(或两者都缺乏)。 上调干细胞受体CD44，同时下调Lgr5+肠道干细胞， 这意味着一种新型的肿瘤起始细胞(TICS)的出现。肿瘤有机体中CD44+的抑制作用 证明其对生长的要求，并支持其生理病理相关性。始终如一地，抑制 体内CD44主要基质配体之一(透明质酸)的表达可消除DKOIEC的间充质表型 肿瘤抑制免疫抑制反应，恢复免疫监视。我们假设 蛋白激酶C/缺失对CD44+/LGR5-TICs的上调在肿瘤的发生发展中起着核心作用 侵略性类型的CRC。MAP激酶的上调与鉴定一起在一种 一系列无偏倚的方法，将转录因子KLF4作为潜在的关键中介 PKc/和CD44的表达，使我们推测pkc/缺乏导致ERK/jnk的激活 触发AP1，并同时诱导KLF4的降解；这两个动作协同驱动CD44 侵袭性大肠癌的表达和间质表型。因此，在这项建议中，我们将 确定CD44在侵袭性/间叶型结直肠癌中的作用(目标1)，以及分子 蛋白激酶C/在这一过程中调节CD44表达和功能的机制(目标2)。成功者 拟议研究的完成将创造一个新的意义和影响范例，这将有助于 对间充质性癌预后不良机制的更全面的认识 这将是设计这种侵袭性肿瘤的新治疗靶点的关键。