title: In vivo RNAi screen identifies NLK as a negative regulator of mesenchymal activity in glioblastoma.
abstract: Glioblastoma (GBM) is the most lethal brain cancer with profound genomic alterations. While the bona fide tumor suppressor genes such as PTEN, NF1, and TP53 have high frequency of inactivating mutations, there may be the genes with GBM-suppressive roles for which genomic mutation is not a primary cause for inactivation. To identify such genes, we employed in vivo RNAi screening approach using the patient-derived GBM xenograft models. We found that Nemo-Like Kinase (NLK) negatively regulates mesenchymal activities, a characteristic of aggressive GBM, in part via inhibition of WNT/β-catenin signaling. Consistent with this, we found that NLK expression is especially low in a subset of GBMs that harbors high WNT/mesenchymal activities. Restoration of NLK inhibited WNT and mesenchymal activities, decreased clonogenic growth and survival, and impeded tumor growth in vivo. These data unravel a tumor suppressive role of NLK and support the feasibility of combining oncogenomics with in vivo RNAi screen.
authors.affiliation: Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.|Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Sa
authors.affiliation: Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
authors.forename: Yeup
authors.initials: Y
authors.lastname: Yoon
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Misuk
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Yeonghwan
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.|Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Jin-Ku
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Gi-Soo
authors.initials: GS
authors.lastname: Kim
authors.affiliation: Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.|Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Suji
authors.initials: S
authors.lastname: Han
authors.affiliation: Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.|Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Woon Jin
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Yong Jae
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.|Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Paddison
authors.affiliation: Division of Cell Regulation Systems, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Ishitani
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jeongwu
authors.initials: J
authors.lastname: Lee
authors.affiliation: Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.|Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.|Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C470551:NLK protein, human; C408347:Nlk protein, mouse; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: Nemo-like kinase; RNA interference screen; glioblastoma; mesenchymal; stemness