Investigating the metastatic drive in pancreas cancer

项目概要 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。尽管如此，仍有少数患者出现局部症状并死亡 破坏性的疾病。这些不同的疾病表现和远处传播与原发性传播的倾向 肿瘤生长还表明，适当应用全身治疗与局部治疗可能会增加 尽管我们正在等待更有效的靶向疗法的开发，但它们的功效并延长了生存期。我们 进行了系统的努力来剖析极端现象背后的病理生理机制 胰腺导管腺癌（PDA）的致死率主要通过基因的产生和研究 该疾病的工程小鼠模型（GEMM）忠实地再现了临床综合征， 人类疾病中的组织病理学、分子特征以及对治疗的反应和耐药性。我们 最近开发了表现上述两种疾病表型的模型系统，并使用 这些系统揭示了由 Runx3/RUNX3 转录因子精心策划的转移程序 控制细胞分裂和传播之间的平衡。该程序可减缓肿瘤的增殖 细胞，同时增加它们传播和成功定殖远距离位点的能力。 Runx3，出演 与点突变 Trp53 和 Dpc4/Smad4 的不同基因剂量相配合，抑制局部生长 远距离传播的代价。在本提案中，我们寻求进一步阐明这一决定背后的机制 胰腺癌疾病行为的节点以及肿瘤抑制因子的不同组合的影响 基因突变可以影响肿瘤上皮细胞和转移灶。这些目标将是 通过 PDA 的新颖 GEMM 的生成和表征来完成；的识别 Runx3相关转录的组成、靶基因占据和转录输出 复合体；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，这些研究将揭示 PDA 非凡能力的潜在机制 转移，识别新的潜在目标来破坏这种能力，并帮助告知适当的选择 临床中已使用的局部治疗方式与全身治疗方式的比较。

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.