000K utf8 1100 2024$c2024-07-01 1500 eng 2050 urn:nbn:de:hbz:465-20250228-154520-0 2051 10.3389/fonc.2024.1406268 3000 Sentek, Hanna 3010 Braun, Annika 3010 Budeus, Bettina 3010 Klein, Diana 4000 Non-small cell lung cancer cells and concomitant cancer therapy induce a resistance-promoting phenotype of tumor-associated mesenchymal stem cells [Sentek, Hanna] 4209 Introduction: 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. Methods: 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. Results: 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. Discussion: 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. 4950 https://doi.org/10.3389/fonc.2024.1406268$xR$3Volltext$534 4950 https://nbn-resolving.org/urn:nbn:de:hbz:465-20250228-154520-0$xR$3Volltext$534 4961 https://duepublico2.uni-due.de/receive/duepublico_mods_00082418 5051 610 5550 adventitia 5550 lung cancer 5550 mesenchymal stem cells 5550 NSCLC 5550 radiotherapy 5550 resistance 5550 SASP 5550 senescence