Characterization of carcinogenesis resistance in Anatolian blind mole-rat mesenchymal stem cells and assessment of transcriptomic signatures.

Abstract

Background: 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).

Methods: 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.

Results: While MNU treatment significantly induced apoptosis and reduced cell viability in human and mouse MSCs, BMR MSCs maintained stable proliferation kinetics, viability, and multilineage 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.

Conclusion: 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.