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

G. G. Jinesh; A. M. Kamat

doi:10.1038/cddiscovery.2015.69

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

G. G. Jinesh, A. M. Kamat

Urology

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

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-endocytosis-p70S6K axis governs subsequent transformation. Disengagement of RalGDS from E-cadherin initiates endocytosis of RalGDS and its novel interaction partners cdc42, VEGFR2, cleaved β-catenin, and PKC-ζ as well as its known interaction partner K-Ras. We also report novel interactions of p45S6K (cleaved p70S6K) and PKM-ζ with PAK-1 filopodia-forming machinery specifically in blebbishields. Thus, a RalGDS-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.

Original language	English (US)
Article number	15069
Journal	Cell Death Discovery
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/cddiscovery.2015.69
State	Published - Dec 12 2016

ASJC Scopus subject areas

Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research

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title = "Endocytosis and serpentine filopodia drive blebbishield-mediated resurrection of apoptotic cancer stem cells",

abstract = "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-endocytosis-p70S6K axis governs subsequent transformation. Disengagement of RalGDS from E-cadherin initiates endocytosis of RalGDS and its novel interaction partners cdc42, VEGFR2, cleaved β-catenin, and PKC-ζ as well as its known interaction partner K-Ras. We also report novel interactions of p45S6K (cleaved p70S6K) and PKM-ζ with PAK-1 filopodia-forming machinery specifically in blebbishields. Thus, a RalGDS-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.",

author = "Jinesh, {G. G.} and Kamat, {A. M.}",

note = "Funding Information: The authors thank Drs Alexandra C Newton, Lawrence A Quilliam, and Philippe Chavrier for plasmids (see Experimental procedures), Dr David J McConkey (The University of Texas MD Anderson Cancer Center) for various reagents, Dr Robert Langley and Mr Kenneth Dunner Jr for help with electron microscopy, Ms Stephanie Deming for editorial help in manuscript preparation, and Ms I-Ling Lee for technical help. This research was supported in part by the National Institutes of Health through MD Anderson{\textquoteright}s Cancer Center Support Grant, CA016672, and used the High-Resolution Electron Microscopy Facility. Publisher Copyright: {\textcopyright} 2016, The Author(s).",

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N2 - 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-endocytosis-p70S6K axis governs subsequent transformation. Disengagement of RalGDS from E-cadherin initiates endocytosis of RalGDS and its novel interaction partners cdc42, VEGFR2, cleaved β-catenin, and PKC-ζ as well as its known interaction partner K-Ras. We also report novel interactions of p45S6K (cleaved p70S6K) and PKM-ζ with PAK-1 filopodia-forming machinery specifically in blebbishields. Thus, a RalGDS-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.

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

Abstract

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