Mechanisms of Epigenetic Plasticity in PDAC

胰腺导管腺癌（PDAC）是人类最致命的癌症之一， 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效应子途径在治疗PDAC中很大程度上无效， 抵抗力的发展。雅普（是相关蛋白），一种致癌转录 调节剂，不仅是PDAC进展所必需的，而且还赋予对PDAC消退的抗性。 致癌Kras信号传导和其他治疗剂在晚期PDAC肿瘤中的作用。使用下一个- 第二代诱导型基因工程小鼠模型，我们发现，即使PDAC 肿瘤依赖于雅普来维持肿瘤生长和存活所必需的转录输出， 具有干/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他们的雅普成瘾晚期PDAC。在这份协议中，我们 提出了一个多方面的努力，以阐明适应性的分子/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 克服对雅普封锁的抵抗另外，我们会用一种诱导型基因谱系- 追踪模型以追踪癌症“干/祖细胞”小生境如何促成PDAC侵袭， 转移和对雅普消融的抗性。这些实验不仅能提供 对PDAC可塑性机制的重要见解，也为潜在的新的 克服PDAC治疗耐药性的策略。

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.