Origins and functions of pancreatic cancer-associated fibroblasts

胰腺癌相关成纤维细胞的起源和功能

• 批准号: 10611388
• 负责人: Mara H. Sherman
• 金额: $ 37.96万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611388
• 关键词: Ablation; Acceleration; Address; Biology; Cancer Etiology; Cell Differentiation process; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Clinic; Complex; Data; Desmoplastic; Development; Disease; Epithelium; Evolution; Extracellular Matrix; Fibroblasts; Gene Expression Profiling; Genetic; Genetic Transcription; Genotype; Goals; Heterogeneity; Immunotherapy; Inflammatory; Lipids; Malignant Neoplasms; Malignant neoplasm of pancreas; Minor; Modeling; Mutation; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Phenotype; Population; Population Heterogeneity; Prognosis; Proliferating; Property; Reaction; Regulation; Reporter; Reporting; Resistance; Role; Route; Sampling; Solid Neoplasm; Source; Stromal Cells; TP53 gene; Testing; Therapeutic Intervention; Time; Tissues; Tumor Immunity; Tumor Promotion; Tumor Tissue; Tumor Volume; United States; Work; cancer cell; cell behavior; cell type; chemotherapy; density; disease phenotype; effective therapy; experimental study; gain of function mutation; immune checkpoint blockade; immunoregulation; improved; in vivo; mortality; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; pancreatic stellate cell; pancreatic tumorigenesis; pharmacologic; programs; rational design; standard of care; stellate cell; targeted treatment; therapeutic target; therapy resistant; transdifferentiation; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression

PROJECT SUMMARY/ABSTRACT The mechanisms underlying evolution of tumor-associated stroma remain poorly understood. In solid tumors featuring a prominent stromal reaction, an improved understanding of the functions and origins of abundant stromal cell types may facilitate the development of new and effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is the quintessence of a fibro-inflammatory malignancy, with 50-90% of tumor volume occupied by a dense, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are the key cell type which drives the stromal reaction in PDAC, and recent reports suggest that stromal CAFs represent a heterogeneous population of cells from diverse origins, potentially including cell types which support and others which suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas which can transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of fibroblasts in the PDAC tumor microenvironment. However, proper lineage tracing studies have never been performed, such that the relative contribution and specific functions of PSCs in the tumor microenvironment are unknown. Here we will take advantage of a novel mouse model we have developed to track PSC differentiation and function during pancreatic tumor progression in vivo. We hypothesize that PSC-derived fibroblasts in the PDAC microenvironment are a pro-inflammatory and tumor-supportive subset of PDAC CAFs, and thus represent a viable therapeutic target. Our preliminary data support the notion that PSCs contribute to only a subset of the CAF population in the tumor microenvironment, and the functions of these distinct populations are entirely unknown. Our data to date also highlight a potential role for genetic alterations in the epithelial compartment in orchestration of stromal fibroblast evolution. PDAC stromal heterogeneity and functional significance will be interrogated with the following specific aims. Aim 1: Determine the role of PSC- derived CAFs in pancreatic tumorigenesis. A novel mouse model will be used to ablate PSC-derived CAFs for the first time and analyze the impact on tumor growth, survival, and organization of the tumor microenvironment. Aim 2: Assess the consequence of tumor genotype in pancreatic cancer stromal evolution. Motivated by preliminary data, we will use our reporter mouse model and patient samples to analyze the interaction between p53 status in tumor cells and stromal CAF evolutionary routes, with important potential implications for tumor phenotype and therapy responses. Aim 3: Define the role of PSC-derived CAFs in therapy response and resistance. As PSC-derived CAFs express a transcriptional program associated with resistance to chemotherapy and immunotherapy, we will determine the effect of these CAFs on treatment response in vivo. These findings will shed light on mechanisms and consequences of stromal evolution during pancreatic tumorigenesis, and potentially identify distinct CAF populations of relevance in additional solid tumors.

项目摘要/摘要 肿瘤相关基质的演变的基础机制仍然鲜为人知。在实体瘤中 具有突出的基质反应，对丰富功能和起源有了改善的理解 基质细胞类型可能有助于开发新的有效疗法。胰管导管 腺癌（PDAC）是纤维炎性恶性肿瘤的精髓，肿瘤体积的50-90％ 被致密的脱肿瘤基质占据。与癌症相关的成纤维细胞（CAF）是关键细胞类型 驱动PDAC中的基质反应，最近的报道表明基质CAF代表异质 来自不同起源的细胞人群，有可能包括支持的细胞类型和其他细胞类型 抑制肿瘤生长。胰腺星状细胞（PSC）是健康胰腺中的脂质细胞，可以 转变为活化的CAF表型。已建议PSC作为主要来源 PDAC肿瘤微环境中的成纤维细胞。但是，适当的谱系追踪研究从未有过 进行的，使PSC在肿瘤微环境中的相对贡献和特定功能是 未知。在这里，我们将利用一种新的鼠标模型来跟踪PSC 体内胰腺肿瘤进展过程中的分化和功能。我们假设PSC衍生 PDAC微环境中的成纤维细胞是PDAC CAFS的促肿瘤和肿瘤支持子集， 因此代表了一个可行的治疗靶标。我们的初步数据支持PSC有助于 仅在肿瘤微环境中的CAF人群的一个子集，这些独特的功能 人口完全未知。迄今为止，我们的数据还强调了遗传改变的潜在作用 基质成纤维细胞演奏的编排中的上皮室。 PDAC基质异质性和 功能意义将通过以下特定目标审问。目标1：确定PSC-的作用 胰腺肿瘤发生中的CAF。新型的鼠标模型将用于消融PSC衍生的CAF 首次分析对肿瘤生长，生存和组织的影响 微环境。目标2：评估胰腺癌基因型肿瘤基因型的结果 进化。由初步数据激励，我们将使用记者鼠标模型和患者样本 分析肿瘤细胞中p53状态与基质CAF进化途径之间的相互作用，重要 对肿瘤表型和治疗反应的潜在影响。目标3：定义PSC衍生的作用 治疗反应和抗性的CAF。正如PSC衍生的CAF表达转录程序 与对化学疗法和免疫疗法的耐药性相关，我们将确定这些CAF的影响 在体内的治疗反应上。这些发现将阐明基质的机制和后果 胰腺肿瘤发生过程中的进化，并有可能确定相关性的不同CAF种群 额外的实体瘤。