Liang Lunxi, Yang Xueer, Yao Shuoyi, Li Xinmeng, Wang Fen
Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Changsha, China.
Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Changsha, China.
Gene. 2025 Mar 10;940:149220. doi: 10.1016/j.gene.2025.149220. Epub 2025 Jan 5.
Lactylation plays an important role in tumor progression. This study aimed to clarify the impact of lactylation on cancer-associated fibroblasts(CAFs).
Single-cell and bulk RNA sequence data, along with survival information, were obtained from TCGA and GEO datasets. Significant lactylation-associated genes were acquired by differential analysis and used to construct a prognostic model via Cox and LASSO regression analyses. Next, single-cell analysis, enrichment and pathway analysis, pseudotemporal trajectory and survival analysis were used to identify significant lactylation-associated fibroblast subclusters in colon cancer. IMvigor210 and PRJEB23709 cohorts were applied to assess the response to immunotherapy. In vitro experiments were conducted to explore how lactylation affect fibroblasts.
We established a lactylation-associated prognostic model with 17 risk genes in TCGA and further validated it in GEO datasets. Single-cell analysis revealed the lactylation level of fibroblasts in colon cancer was greater than that in normal tissues. Moreover, five lactylation-associated fibroblast subclusters were identified via the NMF algorithm. Patients with lower scores of FB_2_CALD1, FB_3_TPM4 and FB_4_AHNAK subclusters had better clinical prognosis in colon cancer and were more likely to benefit from immunotherapy. Further experiments demonstrated that lactylation could enhance the proliferation, migration and invasion ability of fibroblasts and up-regulate the expression of COL1A1, which was similar to the effect of colon cancer cells.
This study identified key fibroblast subclusters with prognostic value and implied that lactylation might help transform fibroblasts into CAFs in colon cancer for the first time, which provides new paths for understanding the evolution of CAFs and cancer therapeutic strategies.
乳酰化在肿瘤进展中起重要作用。本研究旨在阐明乳酰化对癌症相关成纤维细胞（CAFs）的影响。
从TCGA和GEO数据集中获取单细胞和批量RNA序列数据以及生存信息。通过差异分析获得显著的乳酰化相关基因，并通过Cox和LASSO回归分析用于构建预后模型。接下来，使用单细胞分析、富集和通路分析、伪时间轨迹分析和生存分析来识别结肠癌中显著的乳酰化相关成纤维细胞亚群。应用IMvigor210和PRJEB23709队列评估免疫治疗反应。进行体外实验以探索乳酰化如何影响成纤维细胞。
我们在TCGA中建立了一个包含17个风险基因的乳酰化相关预后模型，并在GEO数据集中进一步验证。单细胞分析显示结肠癌中，成纤维细胞的乳酰化水平高于正常组织。此外，通过非负矩阵分解（NMF）算法识别出五个乳酰化相关的成纤维细胞亚群。FB_2_CALD1、FB_3_TPM4和FB_4_AHNAK亚群得分较低的结肠癌患者临床预后较好，且更可能从免疫治疗中获益。进一步实验表明，乳酰化可增强成纤维细胞的增殖、迁移和侵袭能力，并上调COL1A1的表达，这与结肠癌细胞的作用相似。
本研究首次鉴定出具有预后价值的关键成纤维细胞亚群，并表明乳酰化可能有助于结肠癌中把成纤维细胞转变为CAFs，这为理解CAFs的演变和癌症治疗策略提供了新途径。
