Cytoskeleton club Anita Baillet "Septin subcellular partitioning at the core of the mechanobiological stress response in cancer"

Maintenance of cellular mechanical homeostasis is crucial for proper cell functions but can be challenged by internal or external stress factors, including therapy and mechanic stresses related to the tumor environment. 

 

By investigating cytoskeleton-mediated cell adaptation to stress, we previously evidenced a novel mechanism of taxane resistance in breast cancer cells that involves the overexpression of septins, a family of cytoskeleton proteins. Taxanes early makes septins to relocalize from actin stress fibers to microtubules (MTs), counteracting its MT-stabilizing effect and promoting chemoresistance. Interestingly, this fast relocalization was also observed when cells are grown on low-stiffness extracellular matrix (ECM) or overloaded with cytoplasmic lipid droplets. In all stress conditions, the cytoskeleton remodeling is paralleled by a loss and thinning of actin stress fibers and correlates with mechanotransduction abnormalities, altering the transmission of the stress signal to the nucleus.

 

Focal adhesions are less abundant, and nuclear YAP translocation is substantially inhibited. Using Atomic Force Microscopy, we further observed a decrease in cell elasticity, which may result from reorganization of the subcortical actin network. Finally, through analyses of cell shape on micropatterns and Traction Force Microscopy experiments, we demonstrated a decrease in stress fiber tension and cellular contractility. Furthermore, a common transcriptomic signature associated with septin relocalization-mediated alterations in mechanotransduction was identified, highlighting a set of seven genes that were early upregulated both after 24h of Taxol® treatment and during cell culture on a soft matrix. The most significant hits are involved in regulating gene expression (EHF, LINC01348…), cell signaling and plasticity (ABCA1, SERPINB4, ARRDC3…), and in the secretion of indirect modifiers of the ECM (AREG, TNFAIP6…).

 

Overall, this septin relocalization stress response could appear as a general early adaptation mechanism to mechanical stress and might open new therapeutic strategies to limit tumor initiation, progression, and chemoresistance.