Investigating the metastatic drive in pancreas cancer

项目摘要 胰腺癌异常高的转移倾向限制了大多数患者的生命，包括 那些在早期阶段被诊断出来的人。然而，少数患者存在并死于局部 毁灭性的疾病这些不同的疾病表现和远处传播与原发性 肿瘤生长还表明，适当应用全身与局部治疗可能会增加 他们的疗效和延长生存，即使我们等待更有效的靶向治疗的发展。我们 已经进行了系统的努力，以解剖病理生理机制的极端 胰腺导管腺癌（PDA）的致死性主要通过遗传学的产生和研究， 该疾病的工程小鼠模型（GEMM）忠实地再现了临床综合征， 组织病理学、分子特征以及对人类疾病中所见的治疗的反应和抗性。我们 最近开发了显示上述两种疾病表型的模型系统， 这些系统揭示了由Runx 3/RUNX 3转录因子协调的转移程序， 控制着细胞分裂和扩散之间的平衡这个程序减缓了肿瘤的增殖 细胞，同时增加它们的传播能力，并成功地殖民遥远的网站。Runx 3，在 与点突变的Trp 53和不同基因剂量的Dpc 4/Smad 4一致，抑制了局部生长， 远距离传播的代价。在这一建议中，我们寻求进一步揭示这一决定背后的机制 胰腺癌的疾病行为和不同的肿瘤抑制因子组合的影响 基因突变可能对肿瘤上皮细胞和转移性小生境都有影响。这些目标将是 通过生成和表征PDA的新型GEMM来完成; Runx 3相关转录因子的组成、靶基因占有率和转录输出 复合物;以及介导促进转移的细胞行为的细胞外囊泡的表征。 总的来说，这些调查将揭示PDA非凡能力的潜在机制 转移，确定新的潜在目标来破坏这种能力，并帮助通知适当的选择 局部与全身治疗模式的对比已经在临床上使用。

PROJECT SUMMARY The unusually high metastatic proclivity of pancreas cancer is life-limiting for a majority of patients including those diagnosed at early stages. A minority of patients nevertheless present with and succumb to locally destructive disease. These distinct disease presentations and predilections for distant spread versus primary tumor growth also suggest that the appropriate application of systemic versus local therapies might increase their efficacy and prolong survival, even as we await the development of more effective targeted therapies. We have undertaken a systematic effort to dissect the pathophysiologic mechanisms underlying the extreme lethality of pancreatic ductal adenocarcinoma (PDA) primarily through the generation and study of genetically engineered mouse models (GEMMs) of the disease that faithfully recapitulate the clinical syndrome, histopathology, molecular features, and response and resistance to treatments seen in the human disease. We have recently developed model systems that manifest the two disease phenotypes described above and used these systems to uncover a metastatic program orchestrated by the Runx3/RUNX3 transcription factor that governs the balance between cell division and dissemination. This program slows the proliferation of tumor cells while increasing their ability to disseminate and successfully colonize distant sites. Runx3, acting in concert with point-mutant Trp53 and distinct gene dosages of Dpc4/Smad4, suppresses local growth at the expense of distant spread. In this proposal, we seek to further unravel the mechanisms underlying this decision node in pancreas cancer disease behavior and the influences that distinct combinations of tumor suppressor gene mutations can have on both the tumor epithelial cells and the metastatic niche. These aims will be accomplished through the generation and characterization of novel GEMMs of PDA; identification of the composition, target gene occupancy and transcriptional outputs of Runx3-associated transcriptional complexes; and characterization of extracellular vesicles that mediate cell behaviors promoting metastasis. Collectively, these investigations will reveal the mechanisms underlying the extraordinary competency of PDAs to metastasize, identify new potential targets to disrupt this capability, and help inform the appropriate selection of local vs. systemic treatment modalities already in use in the clinic.