Vimentin filaments drive migratory persistence in polyploidal cancer cells
Menée à l'aide de lignées cellulaires de cancer du sein d'origine humaine, cette étude met en évidence un mécanisme par lequel les filaments de vimentine favorisent la migration des cellules cancéreuses polyploïdes et la persistance de cette migration
Polyploidal cells have been shown to correlate with poor patient outcomes in the clinic, as well as with increased chemoresistance and tumorigenicity. They are also implicated in cancer aggression due to their highly migratory phenotype. There is a serious lack of understanding of the underlying biophysical mechanisms that drive their increased migration. Here we address this lack of knowledge and show that vimentin is key to their migratory phenotype, especially in the context of cellular jamming. We also propose a therapeutic avenue that can be adapted in the clinic to mitigate the deleterious effects of these giant cancer cells on patient outcomes.Polyploidal giant cancer cells (PGCCs) are multinucleated chemoresistant cancer cells found in heterogeneous solid tumors. Due in part to their apparent dormancy, the effect of PGCCs on cancer progression has remained largely unstudied. Recent studies have highlighted the critical role of PGCCs as aggressive and chemoresistant cancer cells, as well as their ability to undergo amitotic budding to escape dormancy. Our recent study demonstrated the unique biophysical properties of PGCCs, as well as their unusual migratory persistence. Here we unveil the critical function of vimentin intermediate filaments (VIFs) in maintaining the structural integrity of PGCCs and enhancing their migratory persistence. We performed in-depth single-cell analysis to examine the distribution of VIFs and their role in migratory persistence. We found that PGCCs rely heavily on their uniquely distributed and polarized VIF network to enhance their transition from a jammed to an unjammed state to allow for directional migration. Both the inhibition of VIFs with acrylamide and small interfering RNA knockdown of vimentin significantly decreased PGCC migration and resulted in a loss of PGCC volume. Because PGCCs rely on their VIF network to direct migration and to maintain their enlarged morphology, targeting vimentin or vimentin cross-linking proteins could provide a therapeutic approach to mitigate the impact of these chemoresistant cells in cancer progression and to improve patient outcomes with chemotherapy.All study data are included in the main text and SI Appendix.