Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Haidian District, Beijing, 100142, China.
Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, 100144, China.
J Transl Med. 2024 Jun 20;22(1):587. doi: 10.1186/s12967-024-05391-5.
Colorectal cancer (CRC) is a serious global health burden because of its high morbidity and mortality rates. Hypoxia and massive lactate production are hallmarks of the CRC microenvironment. However, the effects of hypoxia and lactate metabolism on CRC have not been fully elucidated. This study aimed to develop a novel molecular subtyping based on hypoxia-related genes (HRGs) and lactate metabolism-related genes (LMRGs) and construct a signature to predict the prognosis of patients with CRC and treatment efficacy.
Bulk and single-cell RNA-sequencing and clinical data of CRC were downloaded from the TCGA and GEO databases. HRGs and LMRGs were obtained from the Molecular Signatures Database. The R software package DESeq2 was used to perform differential expression analysis. Molecular subtyping was performed using unsupervised clustering. A predictive signature was developed using univariate Cox regression, random forest model, LASSO, and multivariate Cox regression analyses. Finally, the sensitivity of tumor cells to chemotherapeutic agents before and after hypoxia was verified using in vitro experiments.
We classified 575 patients with CRC into three molecular subtypes and were able to distinguish their prognoses clearly. The C1 subtype, which exhibits high levels of hypoxia, has a low proportion of CD8 + T cells and a high proportion of macrophages. The expression of immune checkpoint genes is generally elevated in C1 patients with severe immune dysfunction. Subsequently, we constructed a predictive model, the HLM score, which effectively predicts the prognosis of patients with CRC and the efficacy of immunotherapy. The HLM score was validated in GSE39582, GSE106584, GSE17536, and IMvigor210 datasets. Patients with high HLM scores exhibit high infiltration of CD8 + exhausted T cells (Tex), especially terminal Tex, and oxidative phosphorylation (OXPHOS)-Tex in the immune microenvironment. Finally, in vitro experiments confirmed that CRC cell lines were less sensitive to 5-fluorouracil, oxaliplatin, and irinotecan under hypoxic conditions.
We constructed novel hypoxia- and lactate metabolism-related molecular subtypes and revealed their immunological and genetic characteristics. We also developed an HLM scoring system that could be used to predict the prognosis and efficacy of immunotherapy in patients with CRC.
结直肠癌（CRC）因其高发病率和死亡率，是一个严重的全球健康负担。缺氧和大量乳酸生成是 CRC 微环境的标志。然而，缺氧和乳酸代谢对 CRC 的影响尚未完全阐明。本研究旨在基于缺氧相关基因（HRGs）和乳酸代谢相关基因（LMRGs）开发一种新的分子亚分型，并构建一个预测 CRC 患者预后和治疗效果的签名。
从 TCGA 和 GEO 数据库下载 CRC 的批量和单细胞 RNA 测序及临床数据。从分子特征数据库（MSigDB）中获取 HRGs 和 LMRGs。使用 R 软件包 DESeq2 进行差异表达分析。使用无监督聚类进行分子亚分型。使用单因素 Cox 回归、随机森林模型、LASSO 和多因素 Cox 回归分析开发预测签名。最后，通过体外实验验证缺氧前后肿瘤细胞对化疗药物的敏感性。
我们将 575 例 CRC 患者分为三个分子亚型，可以清楚地区分它们的预后。C1 型表现出高缺氧水平，其 CD8+T 细胞比例较低，巨噬细胞比例较高。C1 型患者的免疫检查点基因表达普遍升高，存在严重的免疫功能障碍。随后，我们构建了一个预测模型，HLM 评分，可有效预测 CRC 患者的预后和免疫治疗的疗效。HLM 评分在 GSE39582、GSE106584、GSE17536 和 IMvigor210 数据集得到验证。HLM 评分高的患者在免疫微环境中表现出高浸润的 CD8+耗竭 T 细胞（Tex），尤其是终末 Tex 和氧化磷酸化（OXPHOS）-Tex。最后，体外实验证实 CRC 细胞系在缺氧条件下对 5-氟尿嘧啶、奥沙利铂和伊立替康的敏感性降低。
我们构建了新的缺氧和乳酸代谢相关分子亚分型，并揭示了它们的免疫学和遗传学特征。我们还开发了 HLM 评分系统，可用于预测 CRC 患者的预后和免疫治疗效果。
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