Mechanisms of Epigenetic Plasticity in PDAC

PDAC表观遗传可塑性机制

基本信息

批准号：
10634498
负责人：
Alessandro Gardini
金额：
$ 48.3万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634498
关键词：
ATAC-seq Ablation Biological Models Bromodomains and extra-terminal domain inhibitor Bypass Characteristics Chromatin Conformation Capture and Sequencing Clinical Complex Dedications Development Disease Outcome Epigenetic Process Equilibrium Extinction Gatekeeping Genes Genetic Genetic Engineering Genetic Screening Genetic Transcription Genomics Grant Homeostasis Human Invaded KRAS oncogenesis Label Lesion Maintenance Malignant - descriptor Malignant Neoplasms Metabolic Modeling Molecular Molecular Target Mus Mutation Necrosis Neoplasm Metastasis Nodule Oncogenic Oncoproteins Oral Output Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Pharmaceutical Preparations Population Proteins Refractory Relapse Reporter Research Resistance Resistance development Role Route Signal Transduction Stress System Techniques Therapeutic Therapeutic Agents Time Tumor Cell Invasion addiction cancer therapy chemical genetics chromatin remodeling driving force effective therapy experimental study flexibility follow-up gain of function improved in vivo in vivo evaluation inhibitor insight interest loss of function mouse model neoplastic cell next generation novel therapeutic intervention oncogene addiction pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model predictive modeling prevent progenitor response small molecule stem stem-like cell synergism theories therapy resistant transcription factor transdifferentiation treatment strategy tumor tumor growth tumor microenvironment tumor progression virtual

项目摘要

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly human cancers and in ~95% of cases driven by oncogenic mutations of Kras. Unfortunately, attempts to directly inhibit oncogenic Kras or Ras effector pathways have been largely ineffective in treating PDAC due to the development of resistance. Yap (Yes-associated-protein), an oncogenic transcription regulator, not only is required for PDAC progression but also confers resistance to extinction of oncogenic Kras signaling and other therapeutic agents in advanced PDAC tumors. Using a next- generation inducible genetic engineered mouse model, we discovered that even though PDAC tumors rely on Yap to maintain the transcriptional output necessary for tumor growth and survival, a subpopulation of tumor cells with stem/progenitor-like characteristics undergo epigenetic reprogramming eventually overcoming their Yap addiction in late stage PDAC. In this grant we propose a multi-faceted effort to elucidate the molecular/cellular drivers of adaptive reprogramming in Yap-ablated, advanced PDAC tumors, and explore novel therapeutic strategies to overcome resistance to Yap blockade. Furthermore, we will use an inducible genetic lineage- tracing model to track how the cancer “stem/progenitor” niches contribute to PDAC invasion, metastasis and resistance to Yap ablation. Together, these experiments will not only provide critical insights into the mechanisms underlying PDAC plasticity, but also inform potential new strategies to overcome therapeutic resistance in PDAC.

胰腺导管腺癌（PDAC）是最致命的人类癌症之一，约为95％由KRAS致癌突变驱动的病例。不幸的是，试图直接抑制致癌性KRAS或RAS效应途径在很大程度上无效地治疗PDAC。抵抗的发展。 YAP（是相关蛋白），一种致癌转录调节器，不仅需要PDAC进展晚期PDAC肿瘤中的致癌KRAS信号传导和其他治疗剂。使用下一个生成诱导的基因工程小鼠模型，我们发现，即使PDAC 肿瘤依靠YAP来维持肿瘤生长和生存所需的转录输出，具有茎/祖细胞样特征的肿瘤细胞的亚群经历表观遗传重新编程最终在晚期PDAC中克服了他们的YAP成瘾。在这笔赠款中，我们提出多方面的努力，以阐明自适应的分子/细胞驱动器重新编程YAP驱动的高级PDAC肿瘤，并探索新型的治疗策略克服对YAP封锁的阻力。此外，我们将使用诱导的遗传谱系追踪模型以跟踪癌症“茎/祖细胞”壁ches如何促进PDAC入侵，转移和抵抗YAP消融。这些实验不仅会提供对PDAC可塑性基本机制的重要见解，但也为潜在的新知识提供了信息克服PDAC治疗性抗性的策略。