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ODZ1 supports glioblastoma progression by enhancing proliferation and migration of cancer stem-like cells

ABSTRACT: The invasion capacity is one of the hallmarks of glioblastoma (GBM) cells. We found that ODZ1 which is mainly expressed in fetal brain, plays a crucial role in the migration and proliferation of GBM stem-like cells (GSCs). Introduction of the entire ODZ1 or its intracellular fragment in ODZ1-deficient cells promotes migration and invasion in 2D and 3D substrates and in chicken embryo and mouse xenograft models. Moreover, ODZ1 increases the proliferation of GSCs in culture and generates bigger tumor masses in the brain of xenografted mice. Consistently, higher levels of ODZ1 are correlated with lower survival both in patients and in xenograft models. On note, ODZ1 promotes the transcriptional activation of RhoA and ODZ1-induced proliferation and invasion activities were blocked by inhibiting RhoA-ROCK axis. Overall, we describe a novel cancer-associated gene involved in the progression of glioblastoma, providing a putative prognostic marker and a new target for therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE65526 | GEO | 2018/02/01

REPOSITORIES: GEO

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Project description:The role of YAP (Yes associated protein 1 gene) and MRTF-A (Megakaryoblastic Leukemia gene, MLK1), two transcriptional co-activators regulated downstream of GPCRs (G-protein coupled receptor) and RhoA, in growth of glioblastoma cells and in vivo GBM tumor development was explored using human glioblastoma cell lines (1321N1) and tumor initiating cells derived from patient derived xenografts (PDX)PDX (GSC-23) cells. Knockdown of these co-activators in PDX cells using shRNA significantly attenuated in vitro proliferation and stemness assessed by limiting dilution and neurosphere formation. Orthotopic xenografts of the MRTF-A and YAP knockdown PDX cells formed significantly smaller tumors with lower morbidity than wild-type cells. In vitro studies of cellular responses to the GPCR agonist sphingosine 1-phosphate (S1P) demonstrated that YAP was required for glioblastoma cell invasion and migration, whereas MRTF-A, was required for cell adhesion. S1P- stimulated proliferation was abolished by knockout of either YAP or MRTF-A. Gene expression analysis by RNA-sequencing of S1P- treated 1321N1 cells in which MRTF-A and or YAP were deleted knockout cells identified 44 genes that were induced through RhoA and highly dependent on YAP, MRTF-A, or both. Knockdown of F3 (tissue factor; TF), a target gene regulated selectively through YAP, when knocked down blocked 1321N1 cell invasion and migration, whereas knockdown of HBEGF (Hheparin binding EGF-like growth factor) (HBEGF), a gene selectively induced through MRTF-A, prevented cell adhesion in response to S1P. Proliferation was sensitive to knockdown of several target genes dually regulated through both YAP and MRTF-A (CCN1 and MYC) or of those regulated by either factor. Expression of these same genes was decreased in tumors from PDX cells lacking YAP or MRTF-A, indicating that these transcriptional pathways are regulated in the in vivo GBM tumor environment and suggesting that their activation through GPCRs and RhoA contributes to growth and maintenance of human GBM.

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ODZ1 supports glioblastoma progression by enhancing proliferation and migration of cancer stem-like cells

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