Journal article
A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance
Developmental cell, Vol.60(11), pp.1532-1549.e7
06/2025
DOI: 10.1016/j.devcel.2025.01.001
PMID: 39862856
Abstract
Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective therapies. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes in vivo and applied this to sonic hedgehog (SHH) medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we identified the voltage-gated potassium channel KCNB2 as a candidate maintenance driver. KCNB2 governs cell volume of MB-propagating cells (MPCs), with KCNB2 depletion causing osmotic swelling, decreased plasma membrane tension, and elevated endocytic internalization of epidermal growth factor receptor (EGFR), thereby mitigating proliferation of MPCs to ultimately impair MB growth. KCNB2 is largely dispensable for mouse development and KCNB2 knockout synergizes with anti-SHH therapy in treating MB. These results demonstrate the utility of the Lazy Piggy functional genomic approach in identifying cancer maintenance drivers and elucidate a mechanism by which potassium homeostasis integrates biomechanical and biochemical signaling to promote MB aggression.
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•Lazy Piggy transposon enables in vivo screening for cancer maintenance drivers•Lazy Piggy screens implicate potassium homeostasis in medulloblastoma maintenance•KCNB2 drives medulloblastoma by controlling biomechanical and biochemical signaling•KCNB2 depletion synergizes with targeted therapy to enhance anti-tumor efficacy
Fan et al. develop a double-jumping transposon to identify cancer maintenance drivers through in vivo functional genomics. The screen identifies potassium channel KCNB2 as a maintenance driver that orchestrates potassium homeostasis, plasma membrane tension, and biochemical signaling to promote medulloblastoma growth.
Details
- Title: Subtitle
- A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance
- Creators
- Jerry J. Fan - University of TorontoAdam J. Dupuy - University of IowaAnders W. Erickson - Hospital for Sick ChildrenJulia Carrillo-Garcia - Hospital for Sick ChildrenXin Wang - Hospital for Sick ChildrenPatryk Skowron - Hospital for Sick ChildrenXian Wang - University of TorontoXin Chen - Shanghai Jiao Tong UniversityGuanqiao Shan - University of TorontoWenkun Dou - University of TorontoShahrzad Bahrampour - Hospital for Sick ChildrenYi Xiong - Xiangya Hospital Central South UniversityWeifan Dong - University of TorontoNamal Abeysundara - Hospital for Sick ChildrenMichelle A. Francisco - Hospital for Sick ChildrenRonwell J. Pusong - Hospital for Sick ChildrenWei Wang - Hospital for Sick ChildrenMiranda Li - Hospital for Sick ChildrenElliot Ying - Hospital for Sick ChildrenRaúl A. Suárez - Hospital for Sick ChildrenHamza Farooq - University of TorontoBorja L. Holgado - Hospital for Sick ChildrenXiaochong Wu - Baylor College of MedicineCraig Daniels - Baylor College of MedicineJuan Cadiñanos - Instituto de Medicina GenómicaAllan Bradley - T-Therapeutics Ltd. One Riverside, Granta Park, Cambridge CB21 6AD, UKAnindya Bagchi - Sanford Burnham Prebys Medical Discovery InstituteBranden S. Moriarity - University of MinnesotaDavid A. Largaespada - University of MinnesotaA. Sorana Morrissy - University of CalgaryVijay Ramaswamy - University of TorontoStephen C. Mack - Hospital for Sick ChildrenLivia Garzia - McGill UniversityPeter B. Dirks - University of TorontoXuejun Li - Xiangya Hospital Central South UniversitySiyi Wanggou - Xiangya Hospital Central South UniversitySean Egan - University of TorontoYu Sun - University of TorontoMichael D. Taylor - Hospital for Sick ChildrenXi Huang - Hospital for Sick Children
- Resource Type
- Journal article
- Publication Details
- Developmental cell, Vol.60(11), pp.1532-1549.e7
- DOI
- 10.1016/j.devcel.2025.01.001
- PMID
- 39862856
- NLM abbreviation
- Dev Cell
- ISSN
- 1534-5807
- eISSN
- 1878-1551
- Publisher
- Elsevier Inc
- Grant note
- Ontario Institute for Cancer Research Translational Research InitiativeCanadian Institute of Health Research Project Grants, b.r.a.i.n.child, and Meagan's HUGNIH: R01NS106155, R01CA159859, R01CA255369 Pediatric Brain Tumour FoundationTerry Fox Research InstituteCanadian Institutes of Health ResearchCure Search Foundationb.r.a.i.n.child, Meagan's Walk, SWIFTY FoundationBrain Tumour CharityGenome CanadaGenome BCGenome QuebecOntario Research FundWorldwide Cancer Research, V-Foundation for Cancer ResearchOntario Institute for Cancer ResearchGovernment of OntarioCanadian Cancer Society Research Institute Impact grantCancer Research UK Brain Tumour AwardStand Up To Cancer (SU2C) St. Baldrick's Pediatric Dream Team Translational Research Grant: SU2C-AACR-DT1113 SU2C Canada Cancer Stem Cell Dream Team Research Funding: SU2C-AACR-DT-19-15 Government of Canada through Genome CanadaStand Up to Cancer is a program of the Entertainment Industry FoundationAmerican Cancer Society Research ProfessorshipRestracomp Scholarship from The Hospital for Sick ChildrenHospital for Sick Children and Dunn with Cancer Research Fellowship from Brain Tumour Foundation of CanadaRuggles Innovation AwardHospital for Sick Children: CPRIT-RR220051 International Postdoc Grant from Swedish Research CouncilChildhood Cancer Research Postdoctoral Fellow Grant from Rally FoundationMelvyn Wolff Chair of Pediatric Neuro-Oncology, Texas Children's Cancer and Hematology Center
This work is supported by Sontag Foundation Distinguished Scientist Award, Ontario Early Researcher Award, Canadian Cancer Society Challenge Grant, Cancer Research Society Operating Grant, Natural Sciences and Engineering Research Council Discovery Grant, American Brain Tumor Association Discovery Grant, Ontario Institute for Cancer Research Translational Research Initiative, Canadian Institute of Health Research Project Grants, b.r.a.i.n.child, and Meagan's HUG to X.H. M.D.T. is supported by the NIH (R01NS106155, R01CA159859, and R01CA255369) , The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, The Canadian Institutes of Health Research, The Cure Search Foundation, Matthew Larson Foundation (IronMatt) , b.r.a.i.n.child, Meagan's Walk, SWIFTY Foundation, The Brain Tumour Charity, Genome Canada, Genome BC, Genome Quebec, the Ontario Research Fund, Worldwide Cancer Research, V-Foundation for Cancer Research, and the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant, a Cancer Research UK Brain Tumour Award, and by a Stand Up To Cancer (SU2C) St. Baldrick's Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113) and SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19-15) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. D.A.L. is supported by an American Cancer Society Research Professorship. J.J.F. is supported by Restracomp Scholarship from The Hospital for Sick Children. Xian Wang is supported by Lap-Chee Tsui Fellowship from The Hospital for Sick Children and Dunn with Cancer Research Fellowship from Brain Tumour Foundation of Canada. A.W.E. is supported by Restracomp Scholarship from The Hospital for Sick Children, the Canada Graduate Scholarship to Honour Nelson Mandela from the Canadian Institutes of Health Research and the Ruggles Innovation Award. J.C.-G. and X.C. are supported by Restracomp Fellowship from The Hospital for Sick Children. S.B. is supported by International Postdoc Grant from Swedish Research Council. N.A. is supported by Childhood Cancer Research Postdoctoral Fellow Grant from Rally Foundation and Restracomp Fellowship from The Hospital for Sick Children. We thank Paul Paroutis and Kimberly Lau at SickKids Imaging Facility for help with confocal imaging and image analysis. Schematics were created using BioRender. M.D.T. is a CPRIT Scholar in Cancer Research (CPRIT-RR220051) and the Cyvia and Melvyn Wolff Chair of Pediatric Neuro-Oncology, Texas Children's Cancer and Hematology Center. X.H. is a catalyst scholar at The Hospital for Sick Children and Canada Research Chair in Cancer Biophysics.
- Language
- English
- Electronic publication date
- 01/20/2025
- Date published
- 06/2025
- Academic Unit
- Anatomy and Cell Biology; Pathology
- Record Identifier
- 9984781270602771
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