Intratumor MAPK and PI3K signaling pathway heterogeneity in glioblastoma tissue correlates with CREB signaling and distinct target gene signatures

Limitations in discovering useful tumor biomarkers and drug targets is not only due to patient-to-patient differences but also due to intratumor heterogeneity. Heterogeneity arises due to the genetic and epigenetic variation of tumor cells in response to microenvironmental interactions and cytotoxic therapy. We explored specific signaling pathway activation in glioblastoma (GBM) by investigating the intratumor activation of the MAPK and PI3K pathways. We present data demonstrating a striking preponderance for mutual exclusivity of MAPK and PI3K activation in GBM tissue, where MAPK activation correlates with proliferation and transcription factor CREB activation and PI3K activation correlates with CD44 expression. Bioinformatic analysis of signaling and CREB-regulated target genes supports the immunohistochemical data, showing that the MAPK-CREB activation correlates with proliferative regions. In-silico analysis suggests that MAPK-CREB signaling activates a pro-inflammatory molecular signature and correlates with a mesenchymal GBM subtype profile, while PI3K-CREB activation correlates with the proneural GBM subtype and a tumor cell invasive gene signature. Overall, the data suggests the existence of intratumor subtype heterogeneity in GBM and that using combinations of both MAPK and PI3K drug inhibitors is necessary for effective targeted therapy. •Activation of PI3K and MAPK in glioblastoma tissue is mostly non-overlapping.•Determination of MAPK and PI3K activation status in glioblastoma tissue using small tissue samples, as represented in tissue microarrays, must be carefully considered given the heterogeneity of activation across tumor tissue.•MAPK activation correlates with proliferation and expression of CREB target genes regulating proliferation and inflammation.•PI3K activation correlates with CD44 expression and CREB target genes regulating invasion and migration.•High MAPK regulated CREB target gene expression correlates with poor survival of glioblastoma patients and is enriched in the mesenchymal glioblastoma subtype.