肿瘤微环境在过去几十年中引起了人们的关注，因为基质细胞对肿瘤的发展、进展和转移、免疫逃避以及癌症治疗耐药性具有显着影响。我们之前报道过，肺驻留间充质干细胞 (MSC) 在非小细胞肺癌 (NSCLC) 进展过程中被动员和激活，甚至可以介导共培养 NSCLC 细胞的辐射耐受性。我们研究了 MSC 如何受到 NSCLC 细胞的影响与癌症（放射）治疗相结合，使用肿瘤条件培养基和 Transwells 间接共培养或直接三维 NSCLC-MSC 球体共培养，以揭示肿瘤相关 MSC 的耐药介导作用。可以观察到 NSCLC 共培养后 MSC 的表型和功能改变，联合放疗 (RT) 后诱导 MSC 衰老。全局基因表达谱与治疗时的基因集富集分析相结合，用于确认受照射的 MSC 的衰老表型，并揭示可介导 NSCLC RT 抵抗的相关衰老相关分泌表型 (SASP) 因子。我们发现衰老肿瘤相关的 MSC 衍生的丝氨酸蛋白酶抑制剂 (serpin) E1/PAI1 是介导 NSCLC 进展和 RT 耐药的潜在 SASP 因子。特定的肿瘤内基质相互作用和细胞类型特异性的促肿瘤发生功能不仅可以改善肺功能癌症分类，甚至可以用于对个体患者进行更精确的分析，最终为非小细胞肺癌患者潜在药物靶点的发现铺平道路。版权所有 © 2024 Sentek、Braun、Budeus 和 Klein。

The tumor microenvironment gained attraction over the last decades as stromal cells significantly impact on tumor development, progression and metastasis, and immune evasion as well as on cancer therapy resistance. We previously reported that lung-resident mesenchymal stem cells (MSCs) were mobilized and activated in non-small cell lung cancer (NSCLC) progression and could even mediate radiation resistance in co-cultured NSCLC cells.We investigated how MSCs were affected by NSCLC cells in combination with cancer (radiation) therapy in indirect co-cultures using tumor-conditioned medium and Transwells or direct three-dimensional NSCLC-MSC spheroid co-cultures in order to unravel the resistance-mediating action of tumor-associated MSCs.Although no obvious phenotypic and functional alterations in MSCs following NSCLC co-culture could be observed, MSC senescence was induced following co-applied radiotherapy (RT). Global gene expression profiling, in combination with gene set enrichment analysis upon treatment, was used to confirm the senescent phenotype of irradiated MSC and to reveal relevant senescence-associated secretory phenotype (SASP) factors that could meditate NSCLC RT resistance. We identified senescent tumor-associated MSC-derived serine proteinase inhibitor (serpin) E1/PAI1 as potential SASP factor mediating NSCLC progression and RT resistance.Specified intra-tumor-stroma interactions and cell type-specific pro-tumorigenic functions could not only improve lung cancer classification but could even be used for a more precise profiling of individual patients, finally paving an additional way for the discovery of potential drug targets for NSCLC patients.Copyright © 2024 Sentek, Braun, Budeus and Klein.