Endosomal pH drives stemness in glioblastoma

By Monish Makena, The Science Advisory Board contributing writer

March 22, 2022 -- A group of researchers has shown that endosomal pH drives stemness in glioblastoma. The group discovered that endosomal Na+/H+ exchanger isoform 9 (NHE9) is a novel driver of stem cell-like characteristics -- or stemness -- in glioblastoma by stabilizing multiple receptor tyrosine kinases (RTKs), according to a recent paper published in PNAS Nexus.

Glioblastoma is the most common brain tumor in adults with current standard care offering only marginal improvement in median survival from 12 to 14.6 months. Cancer stem cells are rare immortal cells within a tumor that can self-renew by dividing and giving rise to many cell types that constitute the tumor. Underlying the inherent resistance to therapy and cancer recurrence is a population of brain tumor initiating cells (BTICs) with stem cell-like characteristics. As a result, a novel, druggable therapeutic target of the BTICs is urgently needed to eliminate the source of resistance and recurrence of the tumor.

The team led by Myungjun Ko, PhD, of the department of neurology in the Johns Hopkins Medical School, used enriched BTICs derived from patient tumor samples in collaboration with Mayo Clinic, which demonstrated that NHE9 is overexpressed in glioblastomas and alkalinizes the lumen of recycling endosomal compartment (PNAS Nexus, March 9).

Interestingly, Ko et al showed that the small increase in the endosomal pH was sufficient to play a pivotal role in pan-specific stabilization of multiple RTKs such as platelet-derived growth factor receptor (PDGFR), insulin-like growth factor receptor 1 (IGF-1R), and insulin receptor (InsulinR) activating the downstream JAK2-STAT3 pathway.

These cellular changes via endosomal pH alkalinization mediated by NHE9 were translated into phenotypic increase in self-renewal and tumorigenic capacity of BTICs in an orthotopic xenograft mouse model. Therefore, targeting endosomal pH may be an attractive therapeutic target that diminishes stemness in glioblastoma.

"Heterogenous expression of RTKs has been an issue in targeted therapies in glioblastoma. This work highlights the role of NHE9 as one of very few targets that can downregulate RTKs in a receptor agnostic manner while diminishing stemness, opening a new avenue for potential therapies," Ko said.

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