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：
10670996
负责人：
Wen-Hao Hsu
金额：
$ 4.16万
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 2023-11-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670996
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 Lipids Maintenance Malignant - descriptor Malignant Neoplasms Mediating Metastatic Neoplasm to the Bone Minority Modeling Molecular Mus Mutation Myelogenous Myeloid-derived suppressor cells Nature Neoplasm Metastasis Oncogenes Oncogenic Outcome Pathway interactions Patients Phase Phenotype Postdoctoral Fellow Proliferating 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 Tumor Promotion Work advanced disease angiogenesis 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.

项目概要而局部期疾病（定义为结直肠癌）患者的 5 年生存率 SEER）为 90%，对于诊断为转移性 CRC 的患者，生存率下降至 14%。迫切需要确定晚期疾病进展及其维持的机制。携带 KRAS 癌基因（以下称为 KRAS*）致癌突变的人类 CRC 同样，我们的 CRC 小鼠模型采用诱导型 KRAS* 设计，发生转移的可能性增加了 25%。 APC 和 p53 等位基因 (iKAP) 的转基因和条件无效等位基因 (iKAP) 揭示了 KRAS* 在驱动中的作用从机制上讲，KRAS* 驱动的癌症转移部分通过通过 IRF2-CXCL3 轴激活癌细胞固有的 TGFβ 信号传导并抑制抗肿瘤免疫不幸的是，针对 KRAS* 或的新兴疗法。 TGFβ 途径在临床中显示出有限的功效，这促使我们识别和验证其他途径 KRAS* 驱动的癌症进展机制，旨在扩大治疗靶点利用 iKAP 模型、功能基因集富集和组织学分析进行转移性 CRC。表达 KRAS* 的 CRC 转移瘤显示出强烈的脂肪生成特征和优势相应地，小鼠共培养肿瘤微环境中的脂肪成纤维细胞和血管生成。使用来自 iKAP 原代细胞系的条件培养基刺激胚胎成纤维细胞分化为具有脂肪细胞和成纤维细胞特征的细胞，即“脂肪成纤维细胞”。在该提案的 F99 阶段，我试图定义表达 KRAS* 的癌细胞驱动脂肪纤维生成的分子机制并了解脂肪成纤维细胞在 KRAS* 驱动的 CRC 进展中的肿瘤生物学作用。由于只有少数人类或小鼠 KRAS* CRC 病例进展为转移性疾病，显然遗传因素 KRAS 激活以外的事件会导致转移，例如，患有或不患有 KRAS* 突变的患者。显示大约 40% 的淋巴结转移率。对此类促转移事件的研究将具有重大意义。通过将诱导型端粒酶逆转录酶 (LSL-mTERT) 整合到我们现有的 iAP 中来促进模型，从而模拟基于端粒的危机和基因组不稳定性，然后是端粒酶重新激活。端粒酶诱导的前列腺癌小鼠模型，危机端粒酶序列产生癌症相关的尽管将基因组不稳定性纳入其中，但基因组畸变并增加了转移潜力。 iAP 模型不会创建一个更像人类的模型，它会提供一个平台来识别扩增和在本提案的 K00 阶段，我寻求设计人类- 像 iAP 模型中的端粒动力学一样，评估基于端粒的危机和端粒酶的影响重新激活驱动转移并调查可能构成转移过程的基因组改变。这可能有助于发现晚期结直肠癌的新治疗目标。