A Feedforward Mechanism Mediated by Mechanosensitive Ion Channel PIEZO1 and Tissue Mechanics Promotes Glioma Aggression
Authors: Ankur Bodalia
Wenkun Dou
Feng Li
Heather Whetstone
Michelle M Kushida
Chi-Chung Hui
Lu-Yang Wang
Wen Chi Yin
Yu Sun
Fiona J Coutinho
Xi Huang
Jerry J Fan
Min Zhu
Peter B Dirks
Diana Draghici
Weifan Dong
Xuejun Li
Yuanquan Song
Xin Chen
Hyun-Kee Min
Siyi Wanggou
Malini Hu
Journal: Neuron (2018)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Drosophila; PIEZO1; Piezo; glioblastoma; glioma
Affiliations: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada., Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China., Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada., Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3G8, Canada., Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada., Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada., Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada., Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3G8, Canada., The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada. Electronic address: .

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. 

Retracted: No

PubPeer comments:
 The use of the term  feedforward in the title manuscript is interesting as the manuscript is actually describing a  positive feedback mechanism. The model in Figure 7 is a perfect example of the output (tissue stiffening) feeding back and enhancing the signaling cascade (to continue driving tissue stiffening). ,