Origins and functions of pancreatic cancer-associated fibroblasts

项目概要/摘要 肿瘤相关间质的演变机制仍然知之甚少。实体瘤 以突出的基质反应为特征，提高了对丰富的 基质细胞类型可以促进新的和有效的疗法的发展。胰腺导管 腺癌（PDAC）是纤维炎性恶性肿瘤的典型，占肿瘤体积的50- 90 被致密的结缔组织基质占据。癌症相关成纤维细胞（CAF）是癌症的关键细胞类型， 驱动PDAC中的基质反应，最近的报道表明，基质CAFs代表了一种异质性的 来自不同来源的细胞群，可能包括支持和其他细胞类型， 抑制肿瘤生长。胰腺星状细胞（PSCs）是健康胰腺中的储脂细胞， 转分化为活化的CAF表型。PSC已被认为是主要来源， 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未被 进行，使得肿瘤微环境中PSC的相对贡献和特异性功能被 未知在这里，我们将利用我们开发的一种新的小鼠模型来跟踪PSC 在胰腺肿瘤体内进展过程中的分化和功能。我们假设PSC衍生的 PDAC微环境中的成纤维细胞是PDACCAF的促炎和肿瘤支持亚群， 因此代表了可行的治疗靶点。我们的初步数据支持PSC有助于 只有肿瘤微环境中CAF群体的一个子集，以及这些不同的功能， 人口完全未知。迄今为止，我们的数据还强调了遗传改变在人类遗传学中的潜在作用。 间质成纤维细胞进化中的上皮区室。PDAC基质异质性和 将以下列具体目标探讨其功能意义。目标1：确定PSC的作用- 衍生CAFs在胰腺肿瘤发生中的作用一种新的小鼠模型将用于消融PSC衍生的CAF 并分析其对肿瘤生长、存活和肿瘤组织的影响 微环境目的2：评估胰腺癌间质中肿瘤基因型的后果 进化受初步数据的启发，我们将使用我们的报告小鼠模型和患者样本， 分析肿瘤细胞中p53状态与间质CAF进化途径之间的相互作用， 对肿瘤表型和治疗反应的潜在影响。目标3：确定PSC衍生的作用 治疗反应和抵抗中的CAF。由于PSC衍生的CAFs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 对体内治疗反应的影响。这些发现将有助于阐明间质细胞凋亡的机制和后果。 在胰腺肿瘤发生过程中的演变，并可能确定不同的CAF人群的相关性， 其他实体瘤。

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.