Poster Presentation 40th Annual Lorne Genome Conference 2019

CREB-mediated transcription integrates diverse upstream pathways to modulate oncogenic signals (#214)

Paul M Daniel 1 , Wayne Phillips 2 , Gulay Filiz 1 , Theo Mantamadiotis 3 4
  1. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
  2. Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  3. Surgery RMH, University of Melbourne, Melbourne, Victoria, Australia
  4. Microbiology & Immunology, University of Melbourne, Melbourne, Victoria, Australia

Cytoplasmic signals transmitted via the PI3K and MAPK pathways converge in the nucleus, onto many transcription factors. A major signalling-transcription hub involves the cAMP Response Element Binding (CREB) protein, a serine/threonine-kinase-inducible transcription factor.

To investigate this signalling-transcription network, we generated a mouse and cell model targeting the inducible expression of a PIK3CA-H1047A oncogenic mutant and deletion of the PI3K negative regulator, PTEN, to neural stem/progenitor cells (NSPCs) [1]. Expression of a Pik3ca-H1047A in NSPCs was enough to generate low-grade tumours but the simultaneous loss of PTEN was required for the development of invasive, high-grade cancer. Tumour tissue and tumour-derived cells showed that there was hyperactivation of not only the PI3K pathway, as expected, but also enhanced MAPK activation, suggesting pathway crosstalk. NSPCs grown as neurospheres showed that the mutations resulted in enhanced proliferation, migration and stem cell potential. To explore the role of CREB, we targeted deletion of CREB in mutant NSPCs and showed that CREB has a dominant role in regulating the proliferation and migration of cells but was not required for tumour initiation.

To further define the role of the PI3K or MAPK pathways and their activation of CREB, we performed a computational analysis of CREB-dependent gene expression in human glioblastoma (GBM) [2]. This analysis showed the enrichment of genes regulating cell cycle control and cell migration. Further analysis of gene modules specifically regulated by each upstream pathway, in cooperation with CREB, showed that each pathway regulated the expression of distinct CREB target genes and cell functions. Migration/invasive tumour cell properties are dominantly regulated by PI3K-CREB signalling-transcription, while MAPK-CREB regulated gene expression dominantly supports tumour cell proliferation. This is the first study demonstrating that the PI3K and MAPK pathways converge onto CREB to modulate distinct transcriptional programs via CREB, which then direct specific cell functions.

  1. DANIEL P, FILIZ G, BROWN DV, CHRISTIE M, WARING PM, ZHANG Y, HAYNES JM, POUTON C, FLANAGAN D, VINCAN E, JOHNS TG, MONTGOMERY K, PHILLIPS WA, MANTAMADIOTIS T. 2018. PI3K Activation in Neural Stem Cells Drives Tumorigenesis which can be Ameliorated by Targeting the cAMP Response Element Binding (CREB) Protein, Neuro-oncology, 20(10):1344-1355
  2. DANIEL PM, FILIZ G, TYMMS MJ, RAMSAY RG, KAYE AH, STYLLI SS, MANTAMADIOTIS T. 2018. Intratumor MAPK and PI3K signaling pathway heterogeneity in glioblastoma tissue correlates with CREB signaling and distinct target gene signatures. Exp Mol Pathol, 105(1):23-31