Embryonic signaling pathways in pancreatic cancer

描述(由申请人提供)：本提案的总体目标是描述胰腺癌形成的潜在机制。胰腺导管腺癌(PDA)是一种对现有治疗方法不敏感的致命性肿瘤。虽然已经做出了重大努力来确定引导这种侵袭性肿瘤形成的分子机制，但从正常胰腺外分泌细胞到肿瘤组织的进展的重要方面仍然未知。我们最近的研究结果表明，在Kras基因突变的背景下，规范的Wnt信号通路在区分正常细胞中腺泡细胞再生和病理性腺泡导管化生(ADM)以及随后的胰腺上皮内瘤变(Panin)/PDA形成方面发挥了关键作用。本研究的目的是明确Wnt信号通路在腺泡细胞再生和病理性ADM、Panin和PDA形成中的作用。初步结果表明，Wnt信号和Kras信号之间存在相互作用，Kras信号是一种已知促进小鼠和人类Panin和PDA形成的途径。为了实现我们的目标，我们建议使用复杂的转基因小鼠模型策略来揭示Wnt信号在正常腺泡再生以及癌症形成和发展中的作用。转基因小鼠模型将被用来在再生胰腺的背景下激活和失活Wnt信号。小鼠模型也将被用来分析Wnt信号在PDA进展中的作用。总之，这项建议旨在了解Kras和Wnt信号之间的相互作用如何影响早期肿瘤前体细胞的形成，以及消除Panin和PDA中的Wnt信号是否最终可能被用作阻止肿瘤进展的新的治疗靶点。 公共卫生相关性：这项建议旨在比较Wnt信号(胚胎信号通路)在正常胰腺再生过程中的作用与导致腺泡导管化生(ADM)、胰腺上皮内瘤变(Panin)以及最终胰腺癌(PDA)形成的病理过程。了解胰腺损伤后正常再生和癌症前体细胞病理形成之间的调控机制非常重要，因为它可能揭示新的方法，要么在早期病变转变为癌症之前识别它们，要么开发新的策略来对抗这种致命的疾病。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to delineate the mechanisms underlying the formation of pancreatic cancer. Pancreatic ductal adenocarcinoma (PDA) is a lethal tumor unreceptive to extant treatment. While significant efforts have been undertaken to define the molecular mechanisms that guide the formation of this aggressive tumor, important aspects of the progression from normal pancreas exocrine cells to neoplastic tissue remain unknown. Our recent results have suggested that the canonical Wnt signaling pathway plays a critical role in distinguishing between acinar cell regeneration in normal cells versus pathological acinar- ductal metaplasia (ADM) followed by pancreatic intraepithelial neoplasia (PanIN)/PDA formation in the context of Kras mutations. The objectives of this proposal are to define the roles of the Wnt signaling pathway during acinar cell regeneration and in the formation of pathological ADM, PanIN, and PDA. Preliminary results suggest interactions between Wnt signaling and Kras signaling, a pathway known to promote PanIN and PDA formation in mouse and human. To accomplish our goals, we propose to use sophisticated transgenic mouse model strategies to unravel the role of Wnt signaling in normal acinar regeneration as well as cancer formation and progression. The transgenic mouse models will be used to activate and inactivate Wnt signaling in the context of a regenerating pancreas. Mouse models will also be employed to analyze the contribution of Wnt signaling to the progression of PDA. In summary, this proposal aims to understand how interactions between Kras and Wnt signaling affect the formation of early tumor progenitors and whether elimination of Wnt signaling in PanIN and PDA could eventually be exploited as a novel therapeutic target to block tumor progression. PUBLIC HEALTH RELEVANCE: This proposal aims to compare the role of Wnt signaling, an embryonic signaling pathway, during normal pancreas regeneration to the pathological processes that result in the formation of acinar-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN), and finally pancreatic adenocarcinoma (PDA). Understanding the mechanisms that regulate the switch between normal pancreas regeneration upon injury and the pathological formation of cancer progenitors is important as it may reveal novel ways to either identify early lesions before they turn into cancer or to develop novel strategies to combat this lethal disease.