Endocytosis and serpentine filopodia drive blebbishield-mediated resurrection of apoptotic cancer stem cells

The blebbishield emergency program helps to resurrect apoptotic cancer stem cells (CSCs) themselves. Understanding the mechanisms behind this program is essential to block resurrection of CSCs during cancer therapy. Here we demonstrate that endocytosis drives serpentine filopodia to construct blebbishields from apoptotic bodies and that a VEGF-VEGFR2-endocytosisp70S6K axis governs subsequent transformation. Disengagement of RaIGDS from E-cadherin initiates endocytosis of RaIGDS and its novel interaction partners cdc42, VEGFR2, cleaved beta-catenin, and PKC-zeta as well as its known interaction partner K-Ras. We also report novel interactions of p45S6K (cleaved p70S6K) and PKM-zeta with PAK-1 filopodia-forming machinery specifically in blebbishields. Thus, a RaIGDS-endocytosis-filopodia-VEGFR2-K-Ras-p70S6K axis drives the blebbishield emergency program, and therapeutic targeting of this axis might prevent resurrection of CSCs during cancer therapy.