Heme overdrive rewires pan-cancer cell metabolism

Abstract

AbstractAll cancers reprogram their metabolism. In this study, we report that all cancer cells employ imbalanced and dynamic heme metabolic pathways essential for their oncogenic growth and coined the term ‘heme overdrive’. Three key characteristics define heme overdrive, i.e., cancer universality, cancer essentiality and cancer specificity. While heme overdrive is absent in diverse differentiated cells or somatic stem cells, it is present in hundreds of cancers, and is delineated in patient-derived tumor progenitor cells by single cell RNAseq. The only exception to heme overdrive in normal tissues is identified in preimplantation human embryos, where heme overdrive likely links to embryonic omnipotency. Among the major drivers are proteins involved in biosynthesis of heme intermediates (hydroxymethylbilane synthase (HMBS) and uroporphyrinogen decarboxylase (UROD)) and heme trafficking (FLVCR1). CRISPR/Cas9 editing to engineer leukemia cells with impaired heme biosynthesis steps confirmed our whole genomic data analyses that heme overdrive is linked to oncogenic states and cellular differentiation. Finally, we devised a novel “bait- and-kill” strategy to target this cancer metabolic vulnerability.One-Sentence SummaryHeme overdrive re-programs cellular metabolism across diverse types of cancer.