Crosstalk between cancer-associated fibroblasts and non-neuroendocrine tumor cells in small cell lung cancer involves in glycolysis and antigen-presenting features

Small cell lung cancer (SCLC) is a highly fatal malignancy, the complex tumor microenvironment (TME) is a critical factor affecting SCLC progression. Cancer-associated fibroblasts (CAFs) are crucial components of TME, yet their role in SCLC and the underlying mechanisms during their interaction with SCLC cells remain to be determined. In this study, a co-culture system comprising MRC5 fibroblasts and SCLC cell lines was constructed. RNA sequencing (RNA-seq) was performed on co-cultured and separately cultured MRC5 and H196 cells to identify differentially expressed genes (DEGs) and enriched signaling pathways. We obsertved that non-neuroendocrine (non-NE) SCLC-derived CAFs exhibited more abundance and DEGs than NE SCLC-derived CAFs did. Enriched glycolysis-related genes, increased glucose uptake, and upregulated glycolytic signaling proteins were found in non-NE SCLC cells when interaction with MRC5 fibroblasts, confirming CAF-mediated glycolysis promotion. Additionally, non-NE SCLC cell-educated CAFs exhibited features of antigen-presenting CAFs (apCAFs), as indicated by the expression of major histocompatibility complex (MHC) molecules. This study emphasizes the pro-tumor function of CAFs in SCLC by promoting glycolysis and impairing T cell function, providing direction for the development of novel therapeutic approaches targeting CAF in SCLC. We performed RNA-sequcing in co-cultured or separately cultured SCLC cell lines H196 and fibroblast MRC5 using BGISEQ platform

小细胞肺癌（Small Cell Lung Cancer, SCLC）是一类高致死性恶性肿瘤，其复杂的肿瘤微环境（Tumor Microenvironment, TME）是影响SCLC进展的关键因素。癌相关成纤维细胞（Cancer-Associated Fibroblasts, CAFs）是TME的重要组成部分，但其在SCLC中的作用及与SCLC细胞互作的潜在机制仍有待明确。本研究构建了包含MRC5成纤维细胞与SCLC细胞系的共培养体系，对共培养及单独培养的MRC5细胞与H196细胞开展RNA测序（RNA-seq），以筛选差异表达基因（DEGs）并富集其相关信号通路。研究观察到，非神经内分泌型（non-neuroendocrine, non-NE）SCLC来源的CAFs较神经内分泌型（neuroendocrine, NE）SCLC来源的CAFs具有更高的丰度与更多的差异表达基因。与MRC5成纤维细胞互作后，非神经内分泌型SCLC细胞中糖酵解相关基因富集、葡萄糖摄取增加以及糖酵解信号蛋白表达上调，证实了CAFs可介导糖酵解过程的增强。此外，经非神经内分泌型SCLC细胞诱导的CAFs呈现出抗原呈递型CAFs（antigen-presenting CAFs, apCAFs）的特征，表现为主要组织相容性复合体（Major Histocompatibility Complex, MHC）分子的表达。本研究阐明了CAFs通过促进糖酵解、损伤T细胞功能在SCLC中发挥的促肿瘤作用，为靶向SCLC中CAFs的新型治疗策略开发指明了方向。本研究采用BGISEQ测序平台，对共培养或单独培养的SCLC细胞系H196与成纤维细胞MRC5进行了RNA测序。