Investigating the metastatic drive in pancreas cancer

项目总结 胰腺癌异常高的转移倾向限制了大多数患者的生命，包括 那些在早期被诊断出来的人。尽管如此，仍有少数患者存在并屈从于当地 破坏性疾病。这些不同的疾病表现和对远距离传播与原发疾病的偏好 肿瘤的生长也表明，适当地应用全身疗法与局部疗法可能会增加。 它们的有效性和延长存活期，即使我们在等待更有效的靶向治疗的发展。我们 已经进行了一项系统的努力来剖析极端的 胰腺导管腺癌(PDA)的致死性主要通过基因的产生和研究 这种疾病的工程化小鼠模型(GEMM)忠实地概括了临床症状， 人类疾病的组织病理学、分子特征以及对治疗的反应和抵抗力。我们 最近开发了显示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转录因子编排的转移程序 控制着细胞分裂和扩散之间的平衡。这项计划减缓了肿瘤的增殖。 同时提高其传播能力，并成功地在遥远的地点定居。RUNX3，代理 与点突变Trp53和不同基因剂量的Dpc4/Smad4协同作用，抑制局部生长 以远距离传播为代价。在这项提案中，我们寻求进一步揭示这一决定背后的机制。 结节在胰腺癌疾病行为中的作用及不同肿瘤抑制因子组合的影响 基因突变既可以对肿瘤上皮细胞产生影响，也可以对转移的壁龛产生影响。这些目标将是 通过产生和表征PDA的新型GEMM来完成；鉴定 Runx3相关转录产物的组成、靶基因占有率和转录输出 复合体；以及介导促进转移的细胞行为的细胞外小泡的特征。 总的来说，这些调查将揭示个人数字助理非凡能力背后的机制 为了转移，确定新的潜在目标来破坏这一能力，并帮助提供适当的选择 已经在临床上使用的局部治疗方式与系统治疗方式的对比。

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.