The metabolic determinants of lung metastasis dissemination

Pancreatic cancer is a highly aggressive tumor, which is usually discovered at a late stage, with metastasis to the liver and lung. Therefore, it is a pressing issue to decipher the distinct mechanisms in which the tumor progress and metastasize. Reactive oxygen species (ROS) have been demonstrated to contribute to cancer cells proliferation, progression and invasion, thus indicating high metastatic capacity. It has been shown at the laboratory that eliminating TIGAR, a Fructose-2,6-biphosphatase which is an important component of the antioxidant defense mechanism, leads to elevation of mitochondrial ROS, in tumors with mutant K-Ras/ mutant p53 drivers. This leads to an increase in lung metastases, whereas the liver metastases remain, compared to TIGAR-expressing tumors. In order to understand the connection between the two findings, we are using both in-vitro and in-vivo approaches to characterize the metabolic changes inflicted by Tigar depletion, both in PDAC and in lung tumors stemming from the same genetic background. Our recent results indicate that the high mitochondrial ROS levels in the cancer cells might support the increase in a lung metastasis specific glycosylation pattern, that guides Tigar-null disseminated tumor cells to the lungs.