Pancreatic Cancer Development: Genetic and Immune Regulation

摘要(总体)： 胰腺导管腺癌(PDAC)是一种致命性疾病，其发生机制尚不清楚 不完全理解。有证据表明，胰腺癌可能是由于腺泡细胞经历了 称为腺泡到导管化生(ADM)的过程，或从导管细胞形成胰腺上皮内的过程 肿瘤(Panins)。突变或突变组合如何促进PDAC的发展及其作用 这一过程中的炎症反应仍不清楚。此外，免疫细胞之间的相互作用，癌症- 相关成纤维细胞(CAF)和癌细胞可以促进PDAC的发展和进展，但 肿瘤微环境(TME)中细胞之间的信号如何影响干细胞仍有待了解 细胞室(‘茎’)被认为是PDAC发育的基础，并促进免疫逃避。因此， 关于管理PDAC发展的基本机制的多个问题仍然存在。 为了应对这些挑战，我们的卓越和高度互动的团队将识别基因和基质(免疫 细胞和CAF)的相互作用和途径，通过使用创新的 小鼠模型和基于人体组织的方法。我们提出了三个项目，以解决以下总体问题 目标： 1.鉴定起始细胞(S)并解构PDAC启动的遗传途径 2.发现与上皮细胞和CAF相互作用的免疫信号促进胰腺癌 发展与主干 3.研究肿瘤遗传学对PDAC免疫生物学及巨噬细胞靶向应答的影响 免疫疗法 将通过行政和生物统计核心(A)组织这些项目的工作，并赋予其权力 由两个研究核心，重点是人体组织采购(核心B)，并使用高维成像 测量组织中细胞和信号的相互作用(CODEX；核心C)。 参与P01的调查人员领导的团队多年来合作卓有成效，并 产生了令人信服的初步数据，支持解开遗传和免疫信号的可能性 PDAC发展的潜在机制，以及为PDAC开发新的免疫治疗策略， 事实证明，它对基于免疫的疗法具有令人沮丧的抗药性。 我们的研究应该广泛地影响胰腺癌生物学，重要的是，阐明相互作用 免疫和非免疫隔间(上皮，CAF)在塑造肿瘤微环境中的作用 在疾病进化过程中。加快发现新的早期诊断或预防策略 疾病，或晚期PDAC的治疗。

Abstract (Overall): Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease whose mechanisms of development remain incompletely understood. Evidence suggests that pancreatic cancers may arise from acinar cells undergoing a process called acinar to ductal metaplasia (ADM) or from ductal cells to give rise to Pancreatic Intraepithelial Neoplasias (PanINs). How mutations or combinations of mutations promote PDAC development and the role of inflammation in the process still remains unclear. Moreover, interactions between immune cells, cancer- associated fibroblasts (CAFs) and cancer cells can promote PDAC development and progression, but much remains to be learned about how signaling between cells in the tumor microenvironment (TME) affects the stem cell compartment (`stemness') thought to underlie PDAC development and promotes immune evasion. Thus, multiple questions about fundamental mechanisms governing PDAC development persist. To address these challenges, our superb and highly interactive team will identify genetic and stromal (immune cells and CAFs) interactions and pathways that regulate the inception and progression of PDAC using innovative mouse models and human tissue-based approaches. We propose three Projects to address the following overall aims: 1. Identify the originating cell(s) and deconstruct genetic pathways underlying PDAC initiation 2. Discover immune signals that cross-talk with epithelial cells and CAFs to promote pancreas cancer development and stemness 3. Investigate the impact of tumor genetics on PDAC immunobiology and response to macrophage-targeted immunotherapy Effort on these projects will be organized through an Administrative and Biostatistics Core (A) and empowered by two Research Cores, focused on human tissue procurement (Core B), and use of high-dimensional imaging to measure cell and signaling interactions in tissues (CODEX; Core C). The participating investigators on this P01 lead teams that have collaborated productively for years and have generated compelling preliminary data that support the potential for unraveling the genetic and immune signaling mechanisms underlying PDAC development, and developing new immunotherapeutic strategies for PDAC, which has proven frustratingly resistant to immuno-based therapies. Our studies should broadly impact pancreas cancer biology and importantly, elucidate the reciprocal interactions between immune and non-immune compartments (epithelial, CAFs) in shaping the tumor microenvironment during disease evolution. accelerate discovery of novel diagnostic or preventive strategies for early-stage disease, or therapeutics for advanced PDAC.