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: 10737898
• 负责人: Mara H. Sherman
• 金额: $ 29.99万
• 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/10737898
• 关键词: Origins; functions; pancreatic; cancer; associated

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.

项目概要/摘要 肿瘤相关基质进化的机制仍然知之甚少。在实体瘤中 具有显着的基质反应，加深了对丰富基质的功能和起源的理解 基质细胞类型可能有助于开发新的有效疗法。胰管 腺癌 (PDAC) 是纤维炎症恶性肿瘤的精髓，占肿瘤体积的 50-90% 被致密的促纤维增生基质占据。癌症相关成纤维细胞 (CAF) 是关键的细胞类型 驱动 PDAC 中的基质反应，最近的报告表明基质 CAF 代表了一种异质性 来自不同来源的细胞群，可能包括支持的细胞类型和其他支持的细胞类型 抑制肿瘤生长。胰腺星状细胞（PSC）是健康胰腺中的脂质储存细胞，可以 转分化为激活的 CAF 表型。 PSC 被认为是主要的来源 PDAC 肿瘤微环境中的成纤维细胞。然而，适当的谱系追踪研究从未被 进行，以便 PSC 在肿瘤微环境中的相对贡献和特定功能 未知。在这里，我们将利用我们开发的新型小鼠模型来追踪 PSC 体内胰腺肿瘤进展期间的分化和功能。我们假设 PSC 衍生 PDAC 微环境中的成纤维细胞是 PDAC CAF 的促炎和肿瘤支持子集， 因此代表了一个可行的治疗靶点。我们的初步数据支持 PSC 有助于的观点 仅肿瘤微环境中 CAF 群体的一个子集，并且这些不同的功能 人口完全未知。迄今为止，我们的数据还强调了基因改变在 基质成纤维细胞进化中的上皮区室。 PDAC 基质异质性和 功能意义将根据以下具体目标进行质疑。目标 1：确定 PSC 的作用 衍生的 CAF 在胰腺肿瘤发生中的作用。一种新型小鼠模型将用于消融 PSC 衍生的 CAF 首次分析对肿瘤生长、存活和肿瘤组织的影响 微环境。目标 2：评估肿瘤基因型对胰腺癌基质的影响 进化。在初步数据的推动下，我们将使用我们的报告小鼠模型和患者样本来 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，具有重要意义 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 治疗反应和抵抗中的 CAF。由于 PSC 衍生的 CAF 表达转录程序 与化疗和免疫治疗的耐药性相关，我们将确定这些 CAF 的作用 关于体内治疗反应。这些发现将揭示间质的机制和后果 胰腺肿瘤发生过程中的进化，并有可能识别与胰腺肿瘤发生相关的不同 CAF 群体 其他实体瘤。