Porphyrin overdrive rewires cancer cell metabolism.
Swamy R AdapaGregory A HunterNarmin E AminChristopher MarinescuAndrew BorskyElizabeth M SagatysSaid M SebtiGary W ReutherGloria C FerreiraRays H Y JiangPublished in: Life science alliance (2024)
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, to accumulate heme intermediates, that is, porphyrins. We coined this essential metabolic rewiring "porphyrin overdrive" and determined that it is cancer-essential and cancer-specific. Among the major drivers are genes encoding mid-step enzymes governing the production of heme intermediates. CRISPR/Cas9 editing to engineer leukemia cell lines with impaired heme biosynthetic steps confirmed our whole-genome data analyses that porphyrin overdrive is linked to oncogenic states and cellular differentiation. Although 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. 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.
Keyphrases
- crispr cas
- papillary thyroid
- photodynamic therapy
- stem cells
- induced apoptosis
- squamous cell
- genome editing
- single cell
- metal organic framework
- cell cycle arrest
- lymph node metastasis
- squamous cell carcinoma
- bone marrow
- transcription factor
- energy transfer
- mesenchymal stem cells
- acute myeloid leukemia
- endoplasmic reticulum stress
- electron transfer
- signaling pathway
- young adults
- oxidative stress
- cancer therapy
- dna methylation
- gene expression
- cell proliferation
- big data
- cell therapy
- quantum dots