Oncogenic Kras drives stromal adipogenesis to promote colorectal cancer (CRC) progression

致癌 Kras 驱动基质脂肪生成，促进结直肠癌 (CRC) 进展

基本信息

批准号：
10528562
负责人：
Wen-Hao Hsu
金额：
$ 4.21万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10528562
关键词：
Address Adipocytes Alleles Automobile Driving Biological Biological Assay Bypass CXCL3 gene Cancer Model Carcinoma Catalogs Cell Culture Techniques Cell Cycle Progression Cell Line Cells Chromosomal Instability Clinic Coculture Techniques Colorectal Cancer Cytokine Gene DNA Sequence Alteration Data Data Set Development Diagnosis Disease Disease Progression Drops Embryo Engineering Event Fibroblasts Functional disorder Gene Expression Gene set enrichment analysis Genes Genetic Genomic Instability Genomics Goals Histologic Human Human Engineering Immune Impairment KRAS oncogenesis KRAS2 gene KRASG12D Lead Lipids Maintenance Malignant - descriptor Malignant Neoplasms Mediating Metastatic Neoplasm to the Bone Metastatic to Minority Modeling Molecular Mus Mutation Myelogenous Myeloid-derived suppressor cells Nature Neoplasm Metastasis Oncogenes Oncogenic Outcome Pathway interactions Patients Phase Phenotype Public Health RNA-Directed DNA Polymerase Recurrence Reporter Research Research Project Grants Role Signal Transduction Stromal Cells Surveys Survival Rate TP53 gene Telomerase The Cancer Genome Atlas Training Transforming Growth Factor beta Transgenes Tumor Biology Tumor Immunity Work advanced disease angiogenesis base cancer cell cell type colon cancer patients colorectal cancer metastasis colorectal cancer progression conditional knockout cytokine design genomic aberrations in silico in vivo lipid biosynthesis lymph nodes metastatic colorectal metastatic process mouse model new therapeutic target novel prevent promoter prostate cancer model recruit single-cell RNA sequencing targeted treatment telomere therapeutic target trait transcription factor tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

Project Summary While the 5-year survival rate for colorectal cancer (CRC) patients with localized stage disease (as defined by SEER) is 90%, this survival rate drops to 14% for patients diagnosed with metastatic CRC. Thus, there is an urgent need to define the mechanisms governing progression to advanced disease and its maintenance. Human CRCs harboring oncogenic mutations in the KRAS oncogene (designated hereafter as KRAS*) are 25% more likely to develop metastases. Similarly, our CRC mouse model, engineered with an inducible KRAS* transgene and conditional null alleles of APC and p53 alleles (iKAP), has revealed a role for KRAS* in driving cancer progression and metastasis. Mechanistically, KRAS*-driven cancer metastasis functions in part by activating cancer cell-intrinsic TGFβ signaling and suppressing anti-tumoral immunity via the IRF2-CXCL3 axis which recruits myeloid derived suppressor cells. Unfortunately, emerging therapies targeting either KRAS* or TGFβ pathways have shown limited efficacy in the clinic, motivating us to identify and validate additional KRAS*-driven cancer progression mechanisms with the goal of expanding the repertoire of therapeutic targets for metastatic CRC. Utilizing the iKAP model, functional gene set enrichment and histological analyses of KRAS*-expressing CRC metastases revealed a strong adipogenesis signature and preponderance of lipofibroblasts and angiogenesis in the tumor microenvironment. Correspondingly, co-culture of mouse embryonic fibroblasts with conditioned media from iKAP primary cell lines stimulated their differentiation into cells with adipocyte and fibroblast traits, i.e., “lipofibroblasts.” In the F99 phase of this proposal, I seek to define the molecular mechanisms by which KRAS*-expressing cancer cells drive lipofibrogenesis and to understand the tumor biological role of lipofibroblasts in KRAS*-driven CRC progression. As only a minority of human or mouse KRAS* CRC cases progress to metastatic disease, clearly genetic events beyond KRAS activation drive metastases. For example, patients with or without KRAS* mutation both show around a 40% lymph node metastatic rate. The study of such pro-metastasis events would be greatly facilitated by incorporating an inducible telomerase reverse transcriptase (LSL-mTERT) into our existing iAP model, thus modeling telomere-based crisis and genome instability followed by telomerase reactivation. In our telomerase-inducible mouse models of prostate cancer, crisis-telomerase sequence generates cancer-relevant genomic aberrations and increases metastatic potential. Although incorporation of genomic instability into the iAP model would not create a more human-like model, it would provide a platform to identify amplifications and deletions associated with the metastatic process. In the K00 phase of this proposal, I seek to engineer human- like telomere dynamics in the iAP model to assess the impact of telomere-based crisis and telomerase reactivation in driving metastasis and to survey the genomic alterations that may underlie the metastatic process. Such efforts may facilitate the discovery of new therapeutic targets for advanced CRC disease.

项目摘要而结直肠癌（CRC）患有局部阶段疾病的5年生存率（如定义 Seer）为90％，该诊断为转移性CRC的患者的生存率下降到14％。那有一个迫切需要定义为晚期疾病进展及其维持的机制。在Kras Oncogene中具有致癌突变的人CRC（以下称为Kras*）是发展转移的可能性高25％。同样，我们的CRC鼠标模型，由可诱导的Kras*设计 APC和p53等位基因（IKAP）的转基因和有条件的无效等位基因已揭示了Kras*在驾驶中的作用癌症进展和转移。从机械上讲，KRAS*驱动的癌症转移部分作用通过IRF2-CXCL3轴激活癌细胞中的TGFβ信号传导和抑制抗肿瘤免疫力这会收集髓样衍生的抑制细胞。不幸的是，针对Kras*或的新兴疗法或 TGFβ途径在诊所中显示出有限的效率，激励我们识别和验证其他 KRAS*驱动的癌症进展机制，目的是扩大治疗靶标的曲目用于转移性CRC。利用IKAP模型，功能基因集富集和组织学分析 Kras*表达CRC转移酶显示出强烈的脂肪形成特征和优势肿瘤微环境中的脂肪纤维细胞和血管生成。相应地，小鼠共培养来自IKAP主细胞系带有条件培养基的胚胎成纤维细胞刺激其分化为具有脂肪细胞和成纤维细胞性状的细胞，即“脂肪纤维细胞”。在该提案的F99阶段，我试图定义表达KRAS*的癌细胞驱动脂能纤维化并了解的分子机制脂肪纤维细胞在KRAS*驱动的CRC进展中的肿瘤生物学作用。由于只有少数人或小鼠kras* CRC病例发展为转移性疾病，因此显然遗传 KRAS激活以外的事件驱动转移。例如，有或没有KRAS*突变的患者都显示约40％的淋巴结转移率。对此类亲构事件的研究将是很棒的通过将诱导型端粒酶逆转录酶（LSL-MTERT）纳入我们现有的IAP来促进模型，从而对基于端粒的危机和基因组不稳定性进行建模，然后进行端粒酶重新激活。在我们的前列腺癌的端粒酶诱导小鼠模型，危机 - 凝集酶序列产生与癌症相关的基因组畸变并增加转移性潜力。尽管将基因组不稳定性纳入 IAP模型不会创建更类似人类的模型，它将提供一个平台来识别放大和与转移过程相关的删除。在该提案的K00阶段，我试图设计人类像IAP模型中的端粒动力学一样，以评估基于端粒的危机和端粒酶的影响驱动转移的重新激活并调查可能是转移过程的基因组改变。这样的努力可能促进针对晚期CRC疾病的新治疗靶标。