• Intercellular mitochondrial transfer from poly-aneuploid cancer cells drives chemotherapy resistance in ovarian cancer

Polyploid cancer cells (PACCs) exhibit distinct morphological and metabolic features that may underlie their ability to evade chemotherapy and support tumor survival. This study investigates the role of key mitotic regulators in the formation of PACCs and their involvement in intercellular mitochondrial transfer. Through siRNA-mediated knockdown experiments, we demonstrated that the depletion of these regulators disrupts mitotic progression and cytokinesis, leading to multinucleation, chromosomal missegregation, and the emergence of tunneling nanotubes (TNTs). PACCs display increased mitochondrial content and enhanced oxidative phosphorylation, indicating elevated metabolic activity. Notably, we identified a robust transfer of mitochondria from PACCs to neighboring cells via TNTs - a process significantly more pronounced than in non-polyploid control cells. Targeted inhibition of TNT formation, specific signaling pathways and key regulators of mitochondrial transfer, including the Hedgehog signaling pathway and ROR1, markedly reduced mitochondrial exchange and decreased chemoresistance in co-culture models. These findings suggest a novel mechanism whereby PACCs promote chemoresistance through mitochondrial transfer and indicate that disrupting this pathway may be a promising strategy to overcome treatment resistance in cancer.