Current efforts in our laboratory are aimed at further identifying the role of lipid metabolism in lung cancer tumorigenesis and maintenance (with emphasis on mutant KRAS lung cancer). We developed a unique lipidomic analytical MS/MS-based platform that allows the identification and quantification of hundreds to thousands of lipids in cancer cell lines and primary lung cancer specimens of patients or of transgenic mice. We use MALDI-IMS technology to confirm spatial localization of lipid species of interest. With this multifaceted approach we determined that mutant KRAS lung cancer relies on a steady supply of fatty acids to repair peroxidated cellular phospholipids, which otherwise would trigger ferroptotic cell death. Accordingly, we found that inhibition of fatty acid synthesis triggers cell death by ferroptosis.
Our work reveals an unexpected relationship between the regulation of cellular metabolism, oxidative stress, lipid metabolism and tumorigenesis. These networks, converge on the Lands cycle, which is an evolutionary conserved mechanism among all eukaryotes to repair oxidative stress damage of cellular phospholipids
We are also aiming to further identify the key components of the Lands cycle and of its regulatory network and their role in tumorigenesis. We hypothesize that the details on how these processes are regulated by oncogenes/tumor suppressors and nutrient availability will provide novel avenues for cancer drug discovery.