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Mechanisms of Epigenetic Plasticity in PDAC

PDAC表观遗传可塑性机制

基本信息

批准号：
10379399
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/10379399
关键词：
ATAC-seq Ablation Biological Models Bypass Characteristics Chromatin Conformation Capture and Sequencing Clinical Complex Development Disease Outcome Epigenetic Process Equilibrium Extinction (Psychology)Gatekeeping Genes Genetic Genetic Engineering Genetic Screening Genetic Transcription Genomics Grant Homeostasis Human 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 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 cells stem-like cell synergism theories therapy resistant transcription factor 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（Pancreatic ductal adencarcinoma， PDAC）是最致命的人类癌症之一，约占95%