# Connexin 43 drives glioblastoma cancer stem cells through a WNK1 signaling axis

> **NIH NIH R03** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $161,000

## Abstract

ABSTRACT
Glioblastoma, the most common primary malignant brain cancer, remains uniformly fatal despite current
standard of care consisting of maximal safe surgical resection followed by chemotherapy and radiation.
Glioblastoma is characterized by a high degree of heterogeneity, including the presence of therapeutically
resistant cancer stem cells (CSCs) that drive tumor recurrence after therapy. CSCs are greatly influenced by
cues received from the surrounding tumor microenvironment, but the results from studies on the role of direct
cell-cell communication through gap junctions in regulating GBM cell fate remain inconsistent. Gap junctions
have canonically been thought of as tumor suppressive due to frequent loss of connexin expression in tumor
cells. However, work from our laboratory and others now shows that connexins can also be tumor promoting in
CSCs in a context- and connexin subunit-specific manner. We have previously reported tumor-promoting roles
for connexin 46 (Cx46) in glioblastoma, Cx26 in triple-negative breast cancer, and Cx25 in leukemia. Here, in
preliminary data, we now show that glioblastoma CSCs from patient-derived xenografts in fact express higher
levels of Cx43 than Cx46, and Cx43 is required for their survival. Mechanistically, Cx43 is required to maintain
expression of MYC, a critical factor for CSCs. This relationship that has not previously been described.
Phosphorylation of the kinase WNK lysine-deficient protein kinase 1 (WNK1) occurs downstream of Cx43 and is
also required for MYC expression. Based on these preliminary data, we hypothesize that Cx43 activates WNK1
to maintain GBM CSC proliferation, survival, and self-renewal by driving gene expression of MYC. We will test
this hypothesis through the following specific aims: 1) test the hypothesis that Cx43 is required for
phosphorylation of WNK1 in an AKT-dependent manner and 2) test the hypothesis that the catalytic activity of
WNK1 is required for Cx43-mediated MYC expression. With these aims, we will continue to uncover a novel
Cx43-WNK1-MYC signaling axis. Due to the difficulty in specifically targeting connexin proteins, the long-term
goal of this project is to identify downstream signaling nodes that are amenable to targeting to develop new
therapeutic options for patients with glioblastoma.

## Key facts

- **NIH application ID:** 10986467
- **Project number:** 1R03NS135197-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Erin E. Mulkearns-Hubert
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $161,000
- **Award type:** 1
- **Project period:** 2024-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10986467

## Citation

> US National Institutes of Health, RePORTER application 10986467, Connexin 43 drives glioblastoma cancer stem cells through a WNK1 signaling axis (1R03NS135197-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10986467. Licensed CC0.

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