A novel, glutathione-dependent metabolic pathway drives metastatic outgrowth in pancreatic cancer

Abstract public domain (NIH RePORTER)

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 differential gene expression analysis of matched primary tumors and metastasis from genetically engineered mouse models of PDA, a novel functional soft-agar screen, and subsequent validation studies in human specimens we identified a novel glutathione-related metabolic pathway specifically activated in metastatic cells. Critically, inducible ablation of two key factors in the pathway, Gstt1 (glutathione S-transferase theta 1) and the aminoacid transporter Slc38a4, that are specifically expressed in metastatic lesions, completely halted the growth of metastases without affecting the primary tumors; these genes are only expressed in normal liver cells, suggesting that metastatic cells co-opt this pathway and repurpose it for metabolic fitness; furthermore, preliminary data indicate that such adaptation drives a novel conjugating activity (glutathyonylation) of matrix proteins including fibronectin 1 (Fn1) to allow metastatic cells to better expand within the extracellular matrix (ECM), all together indicating that these lesions evolve by acquiring non-genetic adaptations. In this proposal, we will take advantage of biochemistry, cell biology, genetically-engineered mouse models and samples from human patients in order to molecularly characterize these factors, with the potential to change treatment for this devastating disease.

Public health relevance public domain (NIH RePORTER)

Pancreatic cancer is the second leading cause of cancer-related death, with less than 5% survival after 5 years; although patients succumb to metastases, 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 screen, we identified a novel metabolic pathway (that includes an aminoacid transporter and a conjugating enzyme) in metastatic lesions, which inhibition completely halted the growth of metastases without affecting the primary tumors; furthermore, preliminary data indicate that they may provide metabolic fitness for metastatic cells to grow in these foreign niches, indicating that these lesions evolve by acquiring non-genetic adaptations. In this proposal, we will take advantage of biochemistry, cell biology, mouse models and samples from human patients in order to molecularly characterize this pathway, with the potential to change treatment for this devastating disease.