Colorectal cancer (CRC) is the third leading cause of cancer-related death in US. Understanding the mechanisms of CRC development is essential to improve treatment. Increased tissue iron in both mice and humans is associated with increased colon tumorigenesis. However, the precise mechanisms for how iron contributes to colon carcinogenesis are still unclear. The metabolic differences between normal and cancer cells are being interrogated to uncover potential new therapeutic approaches. Many tumor cells exhibit increased glucose consumption, glutamine metabolism and nucleotide synthesis. This proposal will test the central hypothesis that iron-driven cellular metabolic reprograming promotes DNA synthesis and colon tumorigenesis. This hypothesis is based on: 1) iron supplement increases, whereas chelation of iron by deferoxamine (DFO) inhibits the growth and cell proliferation of patient-derived CRC colonoids; 2) treating mice with high-iron diet increases, while low-iron diet decreases colon tumor multiplicity, incidence and progression; 3) metabolomics analysis reveals that excess iron impacts glucose-stimulated nucleotide synthesis by promoting hypoxia-independent ?Warburg-like effect? and fueling pentose phosphate pathway in colonoids; 4) iron restriction by DFO leads to glutamine accumulation and reduction of metabolites in nucleotide biosynthesis pathways in colonoids. Based on these observations, the proposal will test the following three Specific Aims: 1) Define the mechanism by which excess iron affects glucose-stimulated DNA biosynthesis in CRC; 2) Study the impact of iron restriction on glutamine-dependent nucleotide synthesis in CRC; 3) Characterize the role of a DNA polymerase in iron-regulated nucleotide metabolism and CRC. We will utilize highly clinic-relevant CRC patient-derived colonoid culture, metabolomics analysis, and various animal models. Accomplishing the above Aims will provide precise molecular mechanisms for how tumor cells are adapted to iron signal to synthesize nucleotides for facilitating tumor proliferation. These studies will fill our knowledge gap of how iron regulates CRC growth and progression.
