Pan-cancer ion transport signature reveals functional regulators of glioblastoma aggression.

Ion channels, transporters, and other ion-flux controlling proteins, collectively comprising the "ion permeome", are common drug targets, however, their roles in cancer remain understudied. Our integrative pan-cancer transcriptome analysis shows that genes encoding the ion permeome are significantly more often highly expressed in specific subsets of cancer samples, compared to pan-transcriptome expectations. To enable target selection, we identified 410 survival-associated IP genes in 33 cancer types using a machine-learning approach. Notably, GJB2 and SCN9A show prominent expression in neoplastic cells and are associated with poor prognosis in glioblastoma, the most common and aggressive brain cancer. GJB2 or SCN9A knockdown in patient-derived glioblastoma cells induces transcriptome-wide changes involving neuron projection and proliferation pathways, impairs cell viability and tumor sphere formation in vitro, perturbs tunneling nanotube dynamics, and extends the survival of glioblastoma-bearing mice. Thus, aberrant activation of genes encoding ion transport proteins appears as a pan-cancer feature defining tumor heterogeneity, which can be exploited for mechanistic insights and therapy development.

Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity.

Major obstacles in brain cancer treatment include the blood-tumor barrier (BTB), which limits the access of most therapeutic agents, and quiescent tumor cells, which resist conventional chemotherapy. Here, we show that Sox2+ tumor cells project cellular processes to ensheathe capillaries in mouse medulloblastoma (MB), a process that depends on the mechanosensitive ion channel Piezo2. MB develops a tissue stiffness gradient as a function of distance to capillaries. Sox2+ tumor cells perceive substrate stiffness to sustain local intracellular calcium, actomyosin tension, and adhesion to promote cellular process growth and cell surface sequestration of ß-catenin. Piezo2 knockout reverses WNT/ß-catenin signaling states between Sox2+ tumor cells and endothelial cells, compromises the BTB, reduces the quiescence of Sox2+ tumor cells, and markedly enhances the MB response to chemotherapy. Our study reveals that mechanosensitive tumor cells construct the BTB to mask tumor chemosensitivity. Targeting Piezo2 addresses the BTB and tumor quiescence properties that underlie treatment failures in brain cancer.

Channeling Force in the Brain: Mechanosensitive Ion Channels Choreograph Mechanics and Malignancies.

Force is everywhere. Through cell-intrinsic activities and interactions with the microenvironment, cells generate, transmit, and sense mechanical forces, such as compression, tension, and shear stress. These forces shape the mechanical properties of cells and tissues. Akin to how balanced biochemical signaling safeguards physiological processes, a mechanical optimum is required for homeostasis. The brain constructs a mechanical optimum from its cellular and extracellular constituents. However, in brain cancer, the mechanical properties are disrupted: tumor and nontumoral cells experience dysregulated solid and fluid stress, while tumor tissue develops altered stiffness. Mechanosensitive (MS) ion channels perceive mechanical cues to govern ion flux and cellular signaling. In this review, we describe the mechanical properties of the brain in healthy and cancer states and illustrate MS ion channels as sensors of mechanical cues to regulate malignant growth. Targeting MS ion channels offers disease insights at the interface of cancer, neuroscience, and mechanobiology to reveal therapeutic opportunities in brain tumors.

Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth.

Ion channels represent a large class of drug targets, but their role in brain cancer is underexplored. Here, we identify that chloride intracellular channel 1 (CLIC1) is overexpressed in human central nervous system malignancies, including medulloblastoma, a common pediatric brain cancer. While global knockout does not overtly affect mouse development, genetic deletion of CLIC1 suppresses medulloblastoma growth in xenograft and genetically engineered mouse models. Mechanistically, CLIC1 enriches to the plasma membrane during mitosis and cooperates with potassium channel EAG2 at lipid rafts to regulate cell volume homeostasis. CLIC1 deficiency is associated with elevation of cell/nuclear volume ratio, uncoupling between RNA biosynthesis and cell size increase, and activation of the p38 MAPK pathway that suppresses proliferation. Concurrent knockdown of CLIC1/EAG2 and their evolutionarily conserved channels synergistically suppressed the growth of human medulloblastoma cells and Drosophila melanogaster brain tumors, respectively. These findings establish CLIC1 as a molecular dependency in rapidly dividing medulloblastoma cells, provide insights into the mechanism by which CLIC1 regulates tumorigenesis, and reveal that targeting CLIC1 and its functionally cooperative potassium channel is a disease-intervention strategy.

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

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.