Characterization of Carcinogenesis Resistance in Anatolian Blind Mole-rat Mesenchymal Stem Cells and Assessment of Transcriptomic Signatures

Mesenchymal stem cells (MSCs) exhibit dual roles in tumor progression and therapy resistance. However, the blind mole-rat (BMR, Nannospalax xanthodon) exhibits extraordinary natural resistance to spontaneous and induced carcinogenesis, making its MSCs a subject of significant therapeutic interest. This study investigates BMR MSCs' and fibroblasts' resistance to the carcinogen N-methyl-N-nitrosourea (MNU). We examined the cellular behavior and transcriptomic expression differences of bone marrow-derived MSCs and also fibroblasts isolated and characterized from blind mole-rats after exposure to the chemical carcinogen MNU. Similar analyses were also performed on mouse, rat, and human-derived MSCs, and expression disparities between species were evaluated. While MNU treatment significantly induced apoptosis and reduced cell viability in human and mouse MSCs, BMR MSCs maintained stable proliferation kinetics, viability, and multi-lineage differentiation potential. Transcriptomic profiling revealed species-specific gene expression patterns, highlighting unique adaptive responses in the BMR. In BMR fibroblasts, MNU treatment suppressed PI3K/Akt signaling and modulated mitochondrial oxidative phosphorylation, whereas BMR MSCs demonstrated a flexible signaling architecture that preserved cellular programming and p53-mediated transcriptional regulation. Cross-species analysis integrated with TCGA datasets identified LAMTOR3 as a critical p53-dependent tumor-protective node. The ability of BMR MSCs to maintain the p53-LAMTOR3 axis following MNU treatment, alongside the suppression of pro-tumoral SMAD signaling, suggests a robust evolutionary strategy to inhibit malignant transformation. These findings provide novel insights into the genomic integrity of the BMR and identify potential biomarkers and therapeutic targets for enhancing cancer resistance.