title: DRR regulates AKT activation to drive brain cancer invasion.
abstract: Glioblastoma (GBM) is the most common and invasive adult brain cancer. The rapid invasion of cancer cells into the normal brain is a major cause of treatment failure, yet the mechanisms that regulate this process are poorly understood. We have identified a novel mechanism of brain cancer invasion. We show that downregulated in renal cell carcinoma (DRR), which is newly expressed in invasive gliomas, recruits AKT to focal adhesions. This DRR- induced pathological relocalization of AKT bypasses commonly altered upstream signaling events and leads to AKT activation and invasion. We also developed an oligonucleotide therapeutic that reduces DRR expression and prevents glioma invasion in an in vivo preclinical model of the disease. Our findings identify DRR as a novel GBM target and show that oligonucleotides targeting DRR is a novel therapeutic approach for the treatment of DRR-positive GBMs.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Dudley
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Sater
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: P U
authors.initials: PU
authors.lastname: Le
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Trinh
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: M S
authors.initials: MS
authors.lastname: Sadr
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Bergeron
authors.affiliation: Department of Chemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: G F
authors.initials: GF
authors.lastname: Deleavey
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Bedell
authors.affiliation: Department of Chemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Damha
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Petrecca
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D009374:Neoplasms, Experimental; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt