Pancreatic Cancer Development: Genetic and Immune Regulation

摘要（总体）： 胰腺导管腺癌（PDAC）是一种致命的疾病，其发展机制仍然存在 不完全理解。有证据表明，胰腺癌可能起源于腺泡细胞经历了一个 称为腺泡到导管化生（ADM）或从导管细胞产生胰腺上皮内 肿瘤（PanIN）。突变或突变的组合如何促进PDAC的发展以及 在这个过程中的炎症仍然不清楚。此外，免疫细胞，癌症之间的相互作用- 相关的成纤维细胞（CAF）和癌细胞可以促进PDAC的发展和进展，但 关于肿瘤微环境（TME）中细胞之间的信号传导如何影响干细胞， 细胞隔室（“干性”）被认为是PDAC发展的基础并促进免疫逃避。因此，在本发明中， 关于管理PDAC开发的基本机制的多个问题仍然存在。 为了应对这些挑战，我们的优秀和高度互动的团队将确定遗传和基质（免疫） 细胞和CAF）的相互作用和途径，调节PDAC的开始和进展，使用创新的 小鼠模型和基于人类组织的方法。我们建议进行三项工程计划，以全面解决以下问题 目的： 1.识别起源细胞并解构PDAC启动的遗传途径 2.发现与上皮细胞和CAFs相互作用以促进胰腺癌的免疫信号 发育与干性 3.研究肿瘤遗传学对PDAC免疫生物学和巨噬细胞靶向治疗反应的影响 免疫治疗 将通过行政和生物统计核心（A）组织这些项目的工作，并授权 由两个研究核心，重点是人体组织采购（核心B）和使用高维成像 以测量组织中的细胞和信号传导相互作用（CODEX;核心C）。 参与P01研究的研究者领导的团队多年来进行了富有成效的合作， 产生了令人信服的初步数据，支持解开遗传和免疫信号的潜力， PDAC发展的潜在机制，并开发新的PDAC免疫策略， 它已经被证明对基于免疫的疗法具有令人沮丧的抵抗力。 我们的研究应该广泛影响胰腺癌生物学，重要的是，阐明相互作用， 免疫和非免疫区室（上皮细胞，CAFs）之间在塑造肿瘤微环境 在疾病演变过程中。加快发现新的诊断或预防策略， 疾病或晚期PDAC的治疗剂。

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.