Porphyrin overdrive rewires pan-cancer cell metabolism

Porphyrin overdrive rewires pan-cancer cell metabolism All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways for their oncogenic growth. We coined this essential metabolic rewiring ‘porphyrin overdrive’ and determined that it is cancer-universal, cancer-essential, and cancer-specific. While porphyrin overdrive is absent in differentiated cells or somatic stem cells, it is present in patient-derived tumor progenitor cells, demonstrated by single cell RNAseq, and in early embryogenesis. Among the major drivers are proteins involved in biosynthesis of heme intermediates and heme trafficking. CRISPR/Cas9 editing to engineer leukemia cells with impaired heme biosynthetic steps confirmed our whole genomic data analyses that porphyrin overdrive is linked to oncogenic states and cellular differentiation. In conclusion, we identified a dependence of cancer cells on non-homeostatic heme metabolism, and we targeted this cancer metabolic vulnerability with a novel “bait-and-kill” strategy to eradicate malignant cells. One-Sentence Summary Porphyrin overdrive reprograms cancer cellular metabolism. ### Competing Interest Statement The authors have declared no competing interest.