Profiling iron-regulated metabolic reprogramming for nucleotide biosynthesis in colon tumors

结直肠癌(CRC)是美国癌症相关死亡的第三大原因。了解 发展结直肠癌的机制对改善治疗至关重要。小鼠和小鼠体内组织铁含量增加 人类与结肠肿瘤发生的增加有关。然而，铁的精确机制 在结肠癌发生中的作用仍不清楚。正常人与癌症患者的代谢差异 正在对细胞进行讯问，以发现潜在的新治疗方法。许多肿瘤细胞表现出 增加葡萄糖消耗、谷氨酰胺代谢和核苷酸合成。这项提案将考验 铁驱动的细胞代谢重编程促进DNA合成和结肠的中心假说 肿瘤发生学。这一假说是基于：1)铁补充量增加，而铁的螯合作用 去铁胺(DFO)抑制患者来源的结直肠癌细胞的生长和增殖；2)治疗小鼠 随着高铁饮食的增加，低铁饮食降低了结肠癌的多发性、发病率和进展性； 代谢组学分析表明，过量的铁通过以下途径影响葡萄糖刺激的核苷酸合成 促进低氧非依赖性的“Warburg-like效应”，为结肠样体中的磷酸戊糖途径提供能量；4) DFO对铁的限制导致谷氨酰胺积聚和核苷酸生物合成中代谢产物的减少 结肠腺样体中的路径。基于这些观察，该提案将检验以下三个具体目标：1) 确定过量铁影响结直肠癌葡萄糖刺激的DNA生物合成的机制；2)研究 铁限制对结直肠癌谷氨酰胺依赖核苷酸合成的影响 DNA聚合酶与铁调节的核苷酸代谢和结直肠癌。我们将利用与临床高度相关的CRC 患者来源的结肠样体培养，代谢组学分析，以及各种动物模型。做到以上几点 AIMS将为肿瘤细胞如何适应铁信号合成提供精确的分子机制 促进肿瘤增殖的核苷酸。这些研究将填补我们对铁如何调节的知识空白 CRC的成长和进步。

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.