Mechanistic Understanding for the Role of Lin28b in Pancreatic Cancer Progression

项目摘要 胰腺导管腺癌(PDA)是美国癌症相关死亡的主要原因， 在过去的三十年里，治疗方法基本保持不变。尽管患者经常死于转移 对于肿瘤，没有专门的诊断标记或治疗策略来治疗转移， 尤其是由于对转移进展的分子驱动因素几乎完全缺乏了解。 利用比较转录组学和一种新的功能软琼脂筛选相结合的方法，我们鉴定了一种 新的因子，DennD5b(含有5b的Denn结构域，一种功能未知的RAB-Global蛋白)，即 在转移灶中特异性表达及其抑制完全阻止转移瘤的生长 不影响原发肿瘤；此外，初步数据表明DennD5b调节血脂 新陈代谢，为这些转移细胞提供代谢适宜性，所有这些都表明这些病变 通过获得非遗传适应来进化。在这个提案中，我们将利用生物化学、细胞 生物学、代谢组学和基因工程小鼠模型，以从分子上表征这一点 因素，有可能改变这种毁灭性疾病的治疗方法。

Project Summary Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer-related death in the US, for which treatment remains basically unchanged in the past three decades. Although patients often die from metastatic lesions, there are no specific diagnostic markers or therapeutic strategies aimed at treating metastases, particularly due to an almost complete lack of knowledge on the molecular drivers of metastatic progression. Using a combination of comparative transcriptomics and a novel functional soft-agar screen, we identified a new factors, DennD5b (DENN domain containing 5b, a RAB-GEF protein of unknown function), that is specifically expressed in metastatic lesions and its inhibition completely halted the growth of metastases without affecting the primary tumors; furthermore, preliminary data indicate that DennD5b modulates lipid metabolism, providing metabolic fitness to these metastatic cells, all together indicating that these lesions evolve by acquiring non-genetic adaptations. In this proposal, we will take advantage of biochemistry, cell biology, metabolomics and genetically-engineered mouse models in order to molecularly characterize this factor, with the potential to change treatment for this devastating disease.