RRC ID 54160
Author Chen X, Wanggou S, Bodalia A, Zhu M, Dong W, Fan JJ, Yin WC, Min HK, Hu M, Draghici D, Dou W, Li F, Coutinho FJ, Whetstone H, Kushida MM, Dirks PB, Song Y, Hui CC, Sun Y, Wang LY, Li X, Huang X.
Title A Feedforward Mechanism Mediated by Mechanosensitive Ion Channel PIEZO1 and Tissue Mechanics Promotes Glioma Aggression.
Journal Neuron
Abstract Alteration of tissue mechanical properties is a physical hallmark of solid tumors including gliomas. How tumor cells sense and regulate tissue mechanics is largely unknown. Here, we show that mechanosensitive ion channel Piezo regulates mitosis and tissue stiffness of Drosophila gliomas, but not non-transformed brains. PIEZO1 is overexpressed in aggressive human gliomas and its expression inversely correlates with patient survival. Deleting PIEZO1 suppresses the growth of glioblastoma stem cells, inhibits tumor development, and prolongs mouse survival. Focal mechanical force activates prominent PIEZO1-dependent currents from glioma cell processes, but not soma. PIEZO1 localizes at focal adhesions to activate integrin-FAK signaling, regulate extracellular matrix, and reinforce tissue stiffening. In turn, a stiffer mechanical microenvironment elevates PIEZO1 expression to promote glioma aggression. Therefore, glioma cells are mechanosensory in a PIEZO1-dependent manner, and targeting PIEZO1 represents a strategy to break the reciprocal, disease-aggravating feedforward circuit between tumor cell mechanotransduction and the aberrant tissue mechanics. VIDEO ABSTRACT.
Volume 100(4)
Pages 799-815.e7
Published 2018-11-21
DOI 10.1016/j.neuron.2018.09.046
PII S0896-6273(18)30848-1
PMID 30344046
MeSH Adult Aged Animals Animals, Genetically Modified Brain Neoplasms / genetics Brain Neoplasms / metabolism* Brain Neoplasms / pathology Drosophila melanogaster Female Glioma / genetics Glioma / metabolism* Glioma / pathology Humans Ion Channels / biosynthesis* Ion Channels / genetics Male Mechanotransduction, Cellular / physiology* Mice, Inbred NOD Mice, SCID Middle Aged Neoplasm Invasiveness / genetics Neoplasm Invasiveness / pathology Tumor Microenvironment / physiology Xenograft Model Antitumor Assays / methods
IF 14.415
Times Cited 26
Drosophila 8486R-1