Yan Hong, Talty Ronan, Jain Abhishek, Cai Yuping, Zheng Jie, Shen Xinyi, Muca Engjel, Paty Philip B, Bosenberg Marcus W, Khan Sajid A, Johnson Caroline H
Department of Environmental Health Sciences, Yale School of Public Health, Yale University, USA.
Department of Pathology, Yale School of Medicine, USA.
bioRxiv. 2023 Mar 1:2023.02.28.530478. doi: 10.1101/2023.02.28.530478.
Aberrant tumor metabolism is a hallmark of cancer in which metabolic rewiring can support tumor growth under nutrient deficient conditions. KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are difficult to treat. The relationship between mutant KRAS and aberrant metabolism in CRCs has not been fully explored and could be a target for intervention. We previously acquired non-targeted metabolomics data from 161 tumor tissues and 39 normal colon tissues from stage I-III chemotherapy naïve CRC patients. In this study, we revealed that tumors from male patients with KRAS mutations only, had several altered pathways that suppress ferroptosis, including glutathione biosynthesis, transsulfuration activity, and methionine metabolism. To validate this phenotype, MC38 CRC cells (KRAS ) were treated with a ferroptosis inducer; RAS-selected lethal (RSL3). RSL3 altered metabolic pathways in the opposite direction to that seen in KRAS mutant tumors from male patients confirming a suppressed ferroptosis metabolic phenotype in these patients. We further validated gene expression data from an additional CRC patient cohort (Gene Expression Omnibus (GEO), and similarly observed differences in ferroptosis-related genes by sex and KRAS status. Further examination of the relationship between these genes and overall survival (OS) in the GEO cohort showed that KRAS mutant tumors are associated with poorer 5-year OS compared to KRAS wild type tumors, and only in male patients. Additionally, high compared to low expression of , which suppressed ferroptosis, were associated with poorer 5-year OS only in KRAS mutant tumors from male CRC patients. Low compared to high expression of was associated with poorer OS for this group. Our results show that KRAS mutant tumors from male CRC patients have suppressed ferroptosis, and gene expression changes that suppress ferroptosis associate with adverse outcomes for these patients, revealing a novel potential avenue for therapeutic approaches.
异常的肿瘤代谢是癌症的一个标志，其中代谢重编程可以在营养缺乏的条件下支持肿瘤生长。KRAS突变发生在所有结直肠癌（CRC）病例的35%-45%中，且难以治疗。CRC中突变型KRAS与异常代谢之间的关系尚未得到充分探索，可能是一个干预靶点。我们之前从I-III期未接受过化疗的CRC患者的161个肿瘤组织和39个正常结肠组织中获取了非靶向代谢组学数据。在本研究中，我们发现，仅KRAS突变的男性患者的肿瘤有几种抑制铁死亡的改变途径，包括谷胱甘肽生物合成、转硫活性和蛋氨酸代谢。为了验证这一表型，用铁死亡诱导剂RAS选择致死（RSL3）处理MC38 CRC细胞（KRAS ）。RSL3改变的代谢途径与男性患者KRAS突变肿瘤中所见的方向相反，证实了这些患者中存在抑制铁死亡的代谢表型。我们进一步验证了来自另一个CRC患者队列（基因表达综合数据库（GEO））的基因表达数据，同样观察到铁死亡相关基因在性别和KRAS状态方面存在差异。对GEO队列中这些基因与总生存期（OS）之间关系的进一步研究表明，与KRAS野生型肿瘤相比，KRAS突变肿瘤与较差的5年OS相关，且仅在男性患者中如此。此外，与低表达相比，抑制铁死亡的 高表达仅在男性CRC患者的KRAS突变肿瘤中与较差的5年OS相关。与高表达相比，该组中低表达与较差的OS相关。我们的结果表明，男性CRC患者的KRAS突变肿瘤具有抑制铁死亡的作用，抑制铁死亡的基因表达变化与这些患者的不良预后相关，揭示了一种新的潜在治疗途径。
