Quantitative in vivo flux analysis reveals tumor and host lipogenic remodeling in KRAS-driven lung cancer

Abstract

Upregulation of de novo lipogenesis is a hallmark of aggressive cancers, underscoring its potential as a therapeutic target. However, metabolic studies of lipogenesis during tumorigenesis in vivo remain limited relative to molecular investigations. Here, we quantitatively examined de novo lipogenic flux in tumors and host metabolic tissues via in vivo isotope tracing in genetically engineered mouse models (GEMMs) of KRAS-driven non-small cell lung cancer. We observed that the increase in tumor lipogenic flux is influenced by specific oncogenic alterations and tumor anatomical location. Notably, allograft tumors displayed lower de novo lipogenesis compared to primary lung tumors in GEMMs. We further examined the direct carbon and hydride sources for the increased tumor lipogenesis and among the substrates tested, lactate and acetate were the predominant direct carbon contributors to tumor fatty acid synthesis. In addition, our data suggest that the oxidative pentose phosphate pathway and one-carbon metabolism make limited contributions to the reducing equivalents supporting de novo fatty acid synthesis under the experimental conditions examined. Furthermore, across different tumor models, we observed substantial impairment in host hepatic de novo lipogenesis, demonstrating remodeling of hepatic and brown adipose tissue lipogenesis in tumor-bearing mice. Collectively, these findings uncover coordinated metabolic adaptations in both tumor and host, providing new insights into cancer lipogenesis and potential therapeutic approaches.