Cholesterol metabolism in mesenchymal colorectal cancer

间叶性结直肠癌中的胆固醇代谢

• 批准号: 10557282
• 负责人: Jorge Moscat
• 金额: $ 52.31万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-09 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557282
• 关键词: Affect; Alanine; Cholesterol; Cholesterol Homeostasis; Colorectal Cancer; Complex; Data; Data Set; Desmoplastic; Diet; Diet Modification; Epithelial Cells; Event; Foundations; Generations; Genes; Genetic Transcription; Goals; Golgi Apparatus; Human; Immunologic Surveillance; Immunosuppression; Intervention; Intestinal Cancer; Intestinal Neoplasms; KRAS2 gene; Knock-out; Lesion; Mediating; Mesenchymal; Metabolic; Microsatellite Repeats; Modeling; Molecular; Mus; Organoids; Pathway interactions; Patients; Phenotype; Phosphorylation; Prognosis; Protein Kinase; Publishing; Regulation; Repression; Role; Route; Sampling; Specimen; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Up-Regulation; addiction; cancer initiation; cancer type; cholesterol biosynthesis; clinically relevant; colon cancer patients; design; effective therapy; experimental study; feeding; human disease; immunosuppressed; in vivo; intestinal epithelium; mouse model; mutant; novel; novel therapeutics; pharmacologic; premalignant; prevent; restraint; targeted treatment; transcriptomics; tumor; tumor initiation; tumor progression; tumorigenesis

PROJECT SUMMARY The overarching goal of this proposal is to identify novel addictions in mesenchymal colorectal cancer (CRC) that will create new vulnerabilities to be targeted therapeutically. This type of aggressive CRC shows a microsatellite stable phenotype, characterized by a strong reactive desmoplastic stroma and immunosuppressed microenvironment. Mesenchymal CRC is enriched in a transcriptomic CMS4 signature, affects about 30-40% of all CRCs with the poorest prognosis, and lacks effective therapies. Our recently published and preliminary data demonstrated that the loss of the two atypical protein kinase Cs (aPKCs; PKC/ and PKC, encoded by PRKCI and PRKCZ genes) drives the mesenchymal phenotype in mouse intestinal tumors. Furthermore, interrogation of human specimens and transcriptional datasets of CRC patients established the aPKCs as new suppressors of mesenchymal CRC. Our data also show that PKC/ is the one whose inactivation unleashes transformation through the mesenchymal route, and new preliminary results, which constitute the foundation of this proposal, demonstrated that aPKC inactivation in several models results in the upregulation of a cholesterol biosynthetic signature and promotes cholesterol synthesis in vivo as evidenced by metabolic tracing experiments in mice. Analysis of human CRC data and samples demonstrate a positive correlation between the activation of the cholesterol biosynthetic pathway and mesenchymal CRC, associated with a negative correlation with aPKC levels. Also, PKC/ directly phosphorylates SCAP, an obligate regulator of SREBP2 processing, which is the master regulator of cholesterol biosynthesis. Therefore, the central hypothesis of this application is that PKC/ by phosphorylating SCAP restrains the cholesterol biosynthetic pathway to repress tumorigenesis in mesenchymal CRC. Building on our strong preliminary data, we will (Aim 1) determine the role of increased cholesterol metabolism in mesenchymal CRC initiation and progression. To that end, we will determine the impact of feeding a high-cholesterol diet (Aim 1.1) or blocking cholesterol metabolism in vivo (Aim 1.2) in tumor initiation and progression of mesenchymal CRC tumors driven by PKC/ deficiency; and determine the human relevance of PKC/-regulated cholesterol metabolism in mesenchymal CRC (Aim 1.3). We will also (Aim 2) determine the molecular mechanisms whereby PKC/ regulates cholesterol biosynthesis in mesenchymal CRC tumorigenesis. Therefore, we will (Aim 2.1) determine the impact of PKC/-mediated SCAP phosphorylation on regulating the SCAP/SREBP2 complex at a mechanistic level; and (Aim 2.2) determine the functional contribution of PKC/-mediated SCAP phosphorylation to CRC in vivo. The results from this proposal will allow the identification of new targets as therapeutic points for intervention in mesenchymal CRC.

项目概要 该提案的总体目标是确定间充质结直肠癌（CRC）的新成瘾性 这将产生新的治疗目标的弱点。 微卫星稳定表型，其特征是强反应性促纤维增生基质和免疫抑制 间充质 CRC 富含转录组 CMS4 特征，影响约 30-40% 所有 CRC 的预后最差，并且缺乏有效的治疗方法。 两个非典型蛋白激酶 C（aPKC；PKC/ 和 PKC，由 PRKCI 编码）的缺失 和 PRKCZ 基因）驱动小鼠肠道肿瘤中的间充质表型。 人类标本和 CRC 患者的转录数据集建立了 aPKC 作为新的抑制因子 我们的数据还表明，PKC/ 的失活会引发转化。 通过间充质途径，以及新的初步结果，构成了该提案的基础， 多个模型中 aPKC 失活证明了胆固醇生物合成上调的结果 小鼠代谢追踪实验证明，它具有特征并促进体内胆固醇合成。 对人类 CRC 数据和样本的分析表明， 胆固醇生物合成途径和间质CRC，与aPKC呈负相关 此外，PKC/ 直接磷酸化 SCAP，SCAP 是 SREBP2 加工的专性调节因子。 因此，本申请的中心假设是 PKC/。 通过磷酸化 SCAP 抑制胆固醇生物合成途径，从而抑制肿瘤发生 基于我们强有力的初步数据，我们将（目标 1）确定增加的作用。 为此，我们将确定间质 CRC 发生和进展中的胆固醇代谢。 高胆固醇饮食（目标 1.1）或阻断体内胆固醇代谢（目标 1.2）对肿瘤的影响 PKC/ 缺陷驱动的间充质 CRC 肿瘤的发生和进展，并确定人类； PKC/ 调节的胆固醇代谢在间质 CRC 中的相关性（目标 1.3）我们还将（目标 2）。 确定 PKC/ 调节间充质 CRC 胆固醇生物合成的分子机制 因此，我们将（目标 2.1）确定 PKC/ 介导的 SCAP 磷酸化对肿瘤发生的影响。 在机械水平上调节 SCAP/SREBP2 复合物；以及（目标 2.2）确定功能； PKC/ 介导的 SCAP 磷酸化对体内 CRC 的贡献 该提案的结果将允许。 确定新的靶点作为间充质结直肠癌干预的治疗点。