Colorectal Cancer Cells Ectopically Express Hepcidin to Sequester Iron

Colorectal cancer cells require iron, an essential micronutrient, and rely on increased uptake of iron from systemic circulation as well as the intestinal lumen. While iron is critical for colorectal cancer tumor growth, the molecular mechanism by which iron is sequestered in tumors and the downstream processes important for survival are not well understood. To investigate the mechanism of intratumoral iron accumulation, Schwartz and colleagues utilized a sporadic mouse model of colorectal cancer, showing that the central iron exporter ferroportin was not expressed in tumor tissue, although abundant in adjacent normal tissue. Epithelial tumor fractions expressed higher levels of Hamp mRNA, encoding hepcidin, a ligand typically expressed by the liver that binds ferroportin at the plasma membrane, leading to ferroportin internalization and degradation. Tissue-specific deletion of Hamp in the colon epithelium led to decreased tumor number, burden, and size. Conversely, when Slc40a1, encoding ferroportin, was deleted in the colon epithelium, tumor burden increased, supporting the importance of tumor cell–derived hepcidin in ferroportin inhibition and subsequent increase in intracellular iron. To identify factors underlying hepcidin upregulation, the intratumoral response to hypoxia was blocked by colon epithelium–specific deletion of Epas1, encoding HIF2α, preventing the tumor-specific increase in Hamp mRNA and suggesting that hypoxia mediated hepcidin expression. Tumors derived from hepcidin- or ferroportin-deficient mice and patient-derived colorectal cancer enteroids displayed significant alterations in pyrimidine and purine metabolism following treatment with the iron chelator deferoxamine (DFO), indicating the importance of iron in nucleotide synthesis. In multiple colorectal cancer cell lines and diverse patient-derived colorectal cancer enteroids, iron depletion via DFO slowed cell growth, whereas growth inhibition was rescued by nucleoside supplementation, providing evidence for the conserved role of iron in nucleotide metabolism. Furthermore, DFO-mediated iron chelation altered mitochondrial metabolism by decreasing respiration, NAD⁺/NADH ratio, and expression of electron transport chain subunits. Together, this work provides insight into iron sequestration and its importance in nucleotide metabolism in colorectal cancer.

Schwartz AJ, Goyert JW, Solanki S, Kerk SA, Chen B, Castillo C, et al. Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells. Nat Metab 2021 June 21 [Epub ahead of print].

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