Csig-09. A Cx43-Wnk1-C-Myc Signaling Axis Drives Glioblastoma Cancer Stem Cell Growth and Survival

Tumors represent highly dynamic systems that rely on the integration of numerous signaling pathways to drive uncontrolled growth and adapt to selective pressures, including those induced by anti-cancer therapies. Glioblastoma (GBM), the most common primary malignant brain tumor, is characterized by a high degree of heterogeneity, including the presence of therapeutically resistant cancer stem cells that drive tumor recurrence after therapy. A frequent genetic modification in GBM is the amplification of the proto-oncogene MYC, which is essential for GBM cancer stem cell proliferation and tumor initiation. However, targeting cancer stem cells by inhibiting MYC has been challenging due to its intrinsically disordered structure as a transcription factor and its multifaceted roles in cell biology. The identification of upstream mechanisms driving MYC expression in GBM may provide additional opportunities for therapeutic development. Here, we provide the first evidence for a non-gap junctional role of connexin 43 (Cx43) in driving MYC expression in patient-derived GBM cancer stem cells. Knockdown of Cx43 reduced GBM cell growth, survival, and tumor initiation through a reduction in expression of MYC and MYC target genes. Cx43 depletion also reduced expression of WNK lysine-deficient protein kinase 1 (WNK1), a kinase shown to be essential for MYC expression in other systems. WNK1 depletion phenocopied Cx43 knockdown and reduced GBM cell growth, tumor initiation, and MYC expression. Together, these results define a novel WNK-MYC signaling network downstream of Cx43 that promotes tumor growth and cancer stem cell phenotypes in GBM and may lead to improved therapies for GBM by targeting this axis.