A Feedforward Mechanism Mediated by Mechanosensitive Ion Channel PIEZO1 and Tissue Mechanics Promotes Glioma Aggression

• Published in: Neuron (Cambridge, Mass.) Vol. 100; no. 4; pp. 799 - 815.e7
• Main Authors: Chen, Xin, Wanggou, Siyi, Bodalia, Ankur, Zhu, Min, Dong, Weifan, Fan, Jerry J., Yin, Wen Chi, Min, Hyun-Kee, Hu, Malini, Draghici, Diana, Dou, Wenkun, Li, Feng, Coutinho, Fiona J., Whetstone, Heather, Kushida, Michelle M., Dirks, Peter B., Song, Yuanquan, Hui, Chi-chung, Sun, Yu, Wang, Lu-Yang, Li, Xuejun, Huang, Xi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.11.2018; Elsevier Limited
• Subjects: Adult; Aged; Animals; Animals, Genetically Modified; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain research; Brain tumors; Breast cancer; Cell adhesion & migration; Cell growth; Drosophila; Drosophila melanogaster; Extracellular matrix; Female; Focal adhesion kinase; Glioblastoma; Glioma; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Glioma cells; Homeostasis; Humans; Insects; ion channel; Ion Channels - biosynthesis; Ion Channels - genetics; Kinases; Male; Mechanical properties; Mechanics; mechanosensation; Mechanotransduction; Mechanotransduction, Cellular - physiology; Medical research; Mice, Inbred NOD; Mice, SCID; Middle Aged; Mitosis; Motility; mouse; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Physiology; Piezo; PIEZO1; Proteins; Software; Solid tumors; Stem cell transplantation; Stem cells; stiffness; tissue mechanics; Tumor cells; Tumor Microenvironment - physiology; Tumors; Xenograft Model Antitumor Assays - methods; mouse; glioblastoma; ion channel; Drosophila; tissue mechanics; Piezo; PIEZO1; glioma; stiffness; mechanosensation
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.09.046

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. [Display omitted] •Drosophila Piezo regulates cell proliferation and tissue stiffening of gliomas•Human PIEZO1 is overexpressed in aggressive gliomas and predicts poor survival•Piezo/PIEZO1 interacts with integrin-FAK signaling to regulate tumor stiffness•PIEZO1 co-opts aberrant tissue mechanics to promote glioma aggression PIEZO1 is an ion channel that converts mechanical stimuli into cellular signaling. Here, Chen et al. perform multi-species studies to define a feedforward circuit mediated by PIEZO1 and tumor tissue mechanics to promote glioma growth.