Ketogenic HMG-CoA lyase and its product ß-hydroxybutyrate promote pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDA) tumor cells are deprived of oxygen and nutrients and therefore must adapt their metabolism to ensure proliferation. In some physiological states, cells rely on ketone bodies to satisfy their metabolic needs, especially during nutrient stress. Here, we show that PDA cells can activate ketone body metabolism and that ß-hydroxybutyrate (ßOHB) is an alternative cell-intrinsic or systemic fuel that can promote PDA growth and progression. PDA cells activate enzymes required for ketogenesis, utilizing various nutrients as carbon sources for ketone body formation. By assessing metabolic gene expression from spontaneously arising PDA tumors in mice, we find HMG-CoA lyase (HMGCL), involved in ketogenesis, to be among the most deregulated metabolic enzymes in PDA compared to normal pancreas. In vitro depletion of HMGCL impedes migration, tumor cell invasiveness, and anchorage-independent tumor sphere compaction. Moreover, disrupting HMGCL drastically decreases PDA tumor growth in vivo, while ßOHB stimulates metastatic dissemination to the liver. These findings suggest that ßOHB increases PDA aggressiveness and identify HMGCL and ketogenesis as metabolic targets for limiting PDA progression.

Role of amino acids in regulation of ROS balance in cancer.

Cancer cells display increased oxidative stress from reactive oxygen species (ROS) and constantly have to counteract them below a tolerable threshold to avoid any toxicity due to overload of ROS. The involvement of ROS in cancer progression from precursor lesions to aggressive tumor and metastasis formation is still debated, but it is recognized that cancer cells succeed to use ROS for their own benefit in circumstances that are tumor cell-type specific. In this review, we focus on amino acids' metabolic pathways that tumor cells activate as antioxidants including cysteine, methionine metabolisms and their connection with the folate, transulfuration pathways and ferroptosis. We discuss how the tumor context definitively dictates the impact of ROS on tumor progression towards a metastatic disease as well as the therapeutic approaches that target ROS to abrogate tumors or limit their aggressiveness.