Mechanisms of Epigenetic Plasticity in PDAC

PDAC表观遗传可塑性机制

• 批准号: 10211135
• 负责人: Alessandro Gardini
• 金额: $ 50.69万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 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/10211135
• 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/antagonist; 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

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 95% 患有胰腺导管腺癌 由 Kras 致癌突变驱动的病例。不幸的是，试图直接抑制 致癌的 Kras 或 Ras 效应通路在治疗 PDAC 方面基本上无效，因为 抵抗力的发展。 Yap（Yes 相关蛋白），一种致癌转录 调节器，不仅是 PDAC 进展所必需的，而且还赋予对灭绝的抵抗力 晚期 PDAC 肿瘤中的致癌 Kras 信号传导和其他治疗药物。使用下一个- 一代诱导型基因工程小鼠模型，我们发现即使 PDAC 肿瘤依靠 Yap 来维持肿瘤生长和存活所需的转录输出， 具有干细胞/祖细胞样特征的肿瘤细胞亚群经历表观遗传 重新编程最终克服了 PDAC 后期的 Yap 成瘾。在这笔赠款中我们 提出多方面的努力来阐明适应性的分子/细胞驱动因素 在 Yap 消融的晚期 PDAC 肿瘤中进行重编程，并探索新的治疗策略 克服雅浦岛封锁的阻力。此外，我们将使用可诱导的遗传谱系- 追踪模型来追踪癌症“干细胞/祖细胞”生态位如何促进 PDAC 侵袭， 转移和对 Yap 消融的抵抗。总之，这些实验不仅将提供 对 PDAC 可塑性潜在机制的重要见解，同时也为潜在的新发现提供了信息 克服 PDAC 治疗耐药的策略。