Alien: Covenant - Cytoneme Biology of Polyaneuploid Cancer Cells to Confer Chemotherapy Resistance

Cytonemes, specialized actin-based filopodial structures, facilitate the intercellular transfer of signaling proteins and organelles. While well-documented in developmental biology, their role in cancer progression remains underexplored. In this study, we investigate the involvement of cytonemes in mediating chemoresistance in High-Grade Serous Ovarian Carcinoma (HGSOC), an aggressive cancer subtype. Our research focuses on poly-aneuploid giant cancer cells (PACCs), which arise under stress conditions and exhibit unique survival mechanisms. We demonstrate that PACCs act as mitochondrial reservoirs, transferring functional mitochondria to neighboring smaller aneuploid cancer cells (ACCs) via cytonemes. This mitochondrial transfer enables ACCs to withstand the cytotoxic effects of chemotherapy, contributing to the development of chemoresistance. Using advanced time-lapse microscopy, we visualized these dynamic intercellular interactions and metabolic adaptations. We further examined the effects of cytoneme inhibitors, such as Vismodegib and ARI-1, under chemotherapeutic stress. Our findings reveal that PACCs form significantly more cytonemes than ACCs and that the inhibition of cytoneme formation disrupts mitochondrial transfer, reducing ACC survival. This study highlights a novel mechanism of chemoresistance mediated by mitochondrial transfer through cytonemes and underscores the therapeutic potential of cytoneme inhibitors in overcoming resistance in HGSOC.