Mechanistic Understanding for the Role of Lin28b in Pancreatic Cancer Progression

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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.