Origins and functions of pancreatic cancer-associated fibroblasts

项目摘要/摘要 肿瘤相关间质演变的机制仍然知之甚少。在实体瘤中 以显著的间质反应为特征，对丰富的功能和起源有了更好的理解 基质细胞类型可能有助于开发新的有效治疗方法。胰管 腺癌(PDAC)是一种典型的纤维炎性恶性肿瘤，占肿瘤体积的50%-90%。 被一层密集的促结缔组织基质占据。肿瘤相关成纤维细胞(CAF)是 驱动PDAC中的间质反应，最近的报告表明间质CAF代表着一种异质性 来自不同来源的细胞群体，可能包括支持的细胞类型和其他 抑制肿瘤生长。胰腺星状细胞(PSCs)是健康胰腺中的储脂细胞，可以 转化为激活的CAF表型。PSCs被认为是主要的来源 PDAC肿瘤微环境中的成纤维细胞。然而，正确的血统追踪研究从来没有 这样，PSCs在肿瘤微环境中的相对贡献和特定功能是 未知。在这里，我们将利用我们开发的用于跟踪PSC的新型鼠标模型 胰腺肿瘤体内发展过程中的分化和功能。我们假设PSC派生的 PDAC微环境中的成纤维细胞是PDAC CAF中促炎症和支持肿瘤的亚群， 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 只有一部分CAF群体在肿瘤微环境中，与这些截然不同的功能 种群是完全未知的。到目前为止，我们的数据也突显了基因改变在 间质成纤维细胞进化中的上皮室。PDAC基质非均质性和 功能意义将以下列具体目标进行审问。目标1：确定PSC的作用- 衍生性CAF在胰腺肿瘤发生中的作用一种新的小鼠模型将被用来消融PSC来源的CAF 并首次分析了其对肿瘤生长、生存和组织的影响 微环境。目的2：评估肿瘤基因分型对胰腺癌间质的影响 进化论。在初步数据的推动下，我们将使用我们的记者鼠模型和患者样本来 分析肿瘤细胞中P53状态和间质CAF进化途径之间的相互作用，具有重要的 对肿瘤表型和治疗反应的潜在影响。目标3：确定PSC派生的角色 CAFS在治疗反应和抵抗中的作用。由于PSC来源的CAF表达转录程序 与化疗和免疫治疗的耐药性有关，我们将确定这些CAF的效果 体内治疗反应的研究。这些发现将有助于阐明间质形成的机制和后果。 在胰腺肿瘤发生过程中的演变，并潜在地识别与胰腺癌相关的不同CAF群体 更多实体瘤。

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.