Epigenetic Regulation of Hemidesmosome Signaling in Pancreatic Cancer

胰腺癌半桥粒信号的表观遗传调控

• 批准号: 10046923
• 负责人: Andrew Liss
• 金额: $ 16.61万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-10 至 2022-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046923
• 关键词: Adenocarcinoma Cell; BRD2 gene; Basement membrane; Biological; Biology; Cancer Etiology; Cell Line; Cells; Cessation of life; Chromatin; Coculture Techniques; Collagen; Collagen Type XVII; Communication; Complex; Desmoplastic; Diagnosis; Disease; Drug Delivery Systems; Enzymes; Epithelial Cells; Exhibits; Extracellular Matrix; Family; Fibroblasts; Fibrosis; Gene Expression; Gene Expression Regulation; Genes; Genetic Enhancer Element; Genetic Transcription; Growth; Growth Factor; Hemidesmosomes; Histology; Human; In Vitro; Individual; Integral Membrane Protein; Lasers; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Modeling; Molecular; Multiprotein Complexes; Neoplastic Stromal Cell; Pancreatic Ductal Adenocarcinoma; Paracrine Communication; Pathway interactions; Patients; Pharmacology; Play; Production; Proteins; Proteomics; Publishing; Role; Sampling; Signal Pathway; Signal Transduction; Source; Stromal Cells; Testing; Therapeutic Intervention; Treatment Efficacy; Tumor Biology; Tumor Volume; United States; Work; cancer cell; cell behavior; cell immortalization; cell motility; clinically relevant; cohort; cytokine; defined contribution; epigenetic regulation; experimental study; insight; interest; migration; novel; promoter; recruit; response; small hairpin RNA; transcriptome; transcriptomics; tumor; tumor growth; tumor microenvironment; tumor xenograft

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers, with less than 8% of patients surviving beyond five years after diagnosis. A key impediment to the treatment of PDAC is a highly desmoplastic tumor stroma. The abundance of non-neoplastic cells and extracellular matrix (ECM) in the stroma have been implicated in promoting aggressive tumor growth and inhibiting effective drug delivery. The ECM has long been thought to be primarily produced by stromal cells, including cancer associated fibroblasts (CAFs). However, our characterization of xenograft tumor models, in vitro co-cultures of CAFs and PDAC cells, and laser capture microdissected tumors has revealed that PDAC cells express a large proportion of the ECM. Furthermore, these studies revealed a CAF-dependent reprogramming of PDAC cells that allows for the expression of ECM components observed in tumors. We have previously demonstrated that the BET family of chromatin adaptors play key roles in the growth of PDAC tumors by regulating pathways in both PDAC and stromal cells. Building on this work, we have found the expression of the ECM in PDAC is broadly regulated by BET proteins. Among these BET-dependent genes are components of the hemidesmosome, a multiprotein complex that mediates signaling from the ECM to the cytoskeletal network of cells. This proposal will examine the mechanisms by which BET proteins mediate the CAF-dependent expression of the ECM in PDAC cells and define the biological role of Collagen XVII, a critical subunit of hemidesmosomes. In Specific Aim 1 of this application, low passage PDAC cell lines and immortalized PDAC-derived CAF cultures will be utilized to examine the transcriptional mechanisms by which CAFs mediate the BET-dependent expression of the ECM- encoding genes in PDAC cells. In Specific Aim 2, we will employ tumor models that temporally regulate the expression of Collagen XVII to define whether CAF-induced expression of Collagen XVII in PDAC cells contribute to PDAC tumor growth. Downstream Collagen XVII signaling pathways will be analyzed in tumors to elucidate the mechanisms by which this signaling contributes to tumor biology.

胰腺导管腺癌 (PDAC) 是最具侵袭性的人类癌症之一，其发病率不到 8% 诊断后存活超过五年的患者。 PDAC 治疗的一个主要障碍是高度 促纤维增生性肿瘤基质。基质中非肿瘤细胞和细胞外基质 (ECM) 的丰度 与促进侵袭性肿瘤生长和抑制有效药物输送有关。 ECM 有 长期以来被认为主要由基质细胞产生，包括癌症相关成纤维细胞（CAF）。 然而，我们对异种移植肿瘤模型、CAF 和 PDAC 细胞体外共培养以及激光的表征 捕获显微解剖的肿瘤揭示了 PDAC 细胞表达大部分 ECM。 此外，这些研究揭示了 PDAC 细胞的 CAF 依赖性重编程，从而允许 在肿瘤中观察到的 ECM 成分的表达。我们之前已经证明了 BET 系列 染色质接头通过调节 PDAC 和 PDAC 中的通路在 PDAC 肿瘤的生长中发挥关键作用 基质细胞。基于这项工作，我们发现 PDAC 中 ECM 的表达广泛受到以下因素的调节： BET 蛋白质。在这些 BET 依赖性基因中，有半桥粒的成分，半桥粒是一种多蛋白 介导从 ECM 到细胞骨架网络的信号传导的复合物。该提案将审查 BET 蛋白介导 PDAC 细胞中 ECM 的 CAF 依赖性表达的机制 定义了 XVII 胶原蛋白（半桥粒的一个关键亚基）的生物学作用。在本次具体目标 1 中 应用程序中，低传代 PDAC 细胞系和永生化 PDAC 衍生的 CAF 培养物将用于 检查 CAF 介导 ECM-BET 依赖性表达的转录机制 PDAC 细胞中的编码基因。在具体目标 2 中，我们将采用暂时调节 XVII 胶原蛋白的表达，以确定 CAF 诱导的 PDAC 细胞中 XVII 胶原蛋白的表达是否有助于 PDAC 肿瘤生长。将分析肿瘤中的下游 XVII 胶原信号通路以阐明 该信号传导促进肿瘤生物学的机制。

项目成果

Transcriptomic Analysis of Laser Capture Microdissected Tumors Reveals Cancer- and Stromal-Specific Molecular Subtypes of Pancreatic Ductal Adenocarcinoma.

激光捕获显微切割肿瘤的转录组分析揭示了胰腺导管腺癌的癌症和基质特异性分子亚型。

• 发表时间: 2021
• 作者: Birnbaum, David J;Begg, Sebastian K S;Finetti, Pascal;Vanderburg, Charles;Kulkarni, Anupriya S;Neyaz, Azfar;Hank, Thomas;Tai, Eric;Deshpande, Vikram;Bertucci, François;Birnbaum, Daniel;Lillemoe, Keith D;Warshaw, Andrew L;Mino
• 通讯作者: Mino

A Lesson in Transcriptional Plasticity: Classical Identity Is Silenced, but Not Lost, in Pancreatic Ductal Adenocarcinoma Cell Lines.

转录可塑性的教训：胰腺导管腺癌细胞系中的经典身份被沉默，但并未丢失。

• 发表时间: 2022-11
• 影响因子: 29.4
• 作者: Baba, Taisuke;Finetti, Pascal;Pancreatic Cancer Group;Lillemoe, Keith D;Warshaw, Andrew L;Fernández;Liss, Andrew S
• 通讯作者: Liss, Andrew S