Folate metabolism in cancer: new opportunities and strategies to exploit metabolic vulnerabilities

Abstract

Our research provides novel insights into how tumor cells alter folate metabolism to support growth and survival, revealing vulnerabilities that can be exploited for therapy. A key finding is the characterization of a novel compound that targets cancer cells resistant to classical antifolates. Furthermore, we demonstrated that the enzyme DHFR2, a poorly characterized paralog of the folate pathway regulator DHFR, plays a key role in regulating mitochondrial homeostasis. Using organoid models, CRISPR strategies, and metabolomics, we showed that DHFR2 has a distinct function from DHFR and that its increased expression supports cancer stem cell traits associated with more aggressive disease. Finally, we demonstrated that, using a novel technology for inducing membrane protein degradation, we can target ‘difficult-to-drug’ amino acid transporters that drive colorectal cancer progression. This thesis thereby advances our understanding of folate metabolism in cancer and identifies novel metabolic vulnerabilities that can be exploited to inhibit tumor growth, overcome resistance, and spare healthy tissues.