Pan-cancer analysis of the ion permeome reveals functional regulators of glioblastoma aggression

Abstract

Ion channels, transporters, and other ion-permeating proteins, collectively comprising the ion permeome (IP), are common drug targets. However, their roles in cancer are understudied. Our integrative pan-cancer analysis shows that IP genes display highly-elevated expression patterns in subsets of cancer samples significantly more often than expected transcriptome-wide. To enable target identification, we identified 410 survival-associated IP genes in 29 cancer types using a machine learning approach. Notably, GJB2 and SCN9A show prominent expression in neoplastic cells and associate with poor prognosis in glioblastoma (GBM), the most common and aggressive brain cancer. GJB2 or SCN9A knockdown in patient-derived GBM cells induces transcriptome-wide changes involving neural projection and proliferation pathways, impairs cell viability and tumor sphere formation, mitigates tunneling nanotube formation, and extends the survival of GBM-bearing mice. Thus, aberrant activation of IP genes appears as a pan-cancer feature of tumor heterogeneity that can be exploited for mechanistic insights and therapy development.

Neuroscience and oncology: state-of-the-art and new perspectives

“…The importance for tumor biology was demonstrated by regional death of network-connected tumor cells that occurred specifically after ablation of the periodic, pacemaker-like cells, and by reduction of glioblastoma growth in mice by pharmacological or genetic interference with KCa3.1 [11 ▪ ]. Interestingly, KCNN4 and also gap junction proteins (which are crucial for cell-cell connections with TMs) were among the five top survival-associated genes of the ion permeome in glioblastoma [13].…”

“…&]. Interestingly, KCNN4 and also gap junction proteins (which are crucial for cell-cell connections with TMs) were among the five top survival-associated genes of the ion permeome in glioblastoma[13].Moreover, single glioblastoma cells that are not connected to the tumor network are the main drivers of the efficient brain invasion observed in this disease, by hijacking neuronal/neural mechanisms on three layers: by residing in plastic cell states that are closest to neural progenitor cell-or neuronal-like states; by using cellular mechanisms of invasivity of immature neurons; and by neuron-glioma synapses (see next paragraph)[14 & …”