A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance

Jerry J Fan¹, Anders W Erickson², Julia Carrillo-Garcia², Xin Wang², Patryk Skowron², Xian Wang³, Xin Chen⁴, Guanqiao Shan⁵, Wenkun Dou⁵, Shahrzad Bahrampour², Yi Xiong⁶, Weifan Dong¹, Namal Abeysundara², Michelle A Francisco², Ronwell J Pusong², Wei Wang², Miranda Li², Elliot Ying², Raúl A Suárez², Hamza Farooq⁷, Borja L Holgado², Xiaochong Wu⁸, Craig Daniels⁸, Adam J Dupuy⁹, Juan Cadiñanos¹⁰, Allan Bradley¹¹, Anindya Bagchi¹², Branden S Moriarity¹³, David A Largaespada¹³, A Sorana Morrissy¹⁴, Vijay Ramaswamy¹⁵, Stephen C Mack¹⁶, Livia Garzia¹⁷, Peter B Dirks¹⁸, Xuejun Li¹⁹, Siyi Wanggou⁶, Sean Egan²⁰, Yu Sun⁵, Michael D Taylor²¹, Xi Huang²²

Affiliations

¹ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
² Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
³ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁴ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
⁵ Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁶ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
⁷ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁸ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Texas Children's Cancer and Hematology Center, Houston, TX 77030, USA; Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, TX 77030, USA.
⁹ Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52246, USA.
¹⁰ Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo 33193, Spain.
¹¹ T-Therapeutics Ltd. One Riverside, Granta Park, Cambridge CB21 6AD, UK.
¹² Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
¹³ Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
¹⁴ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4Z6, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 2T8, Canada.
¹⁵ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
¹⁶ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Developmental Neurobiology, Neurobiology and Brain Tumor Program, Center of Excellence in Neuro-Oncology Sciences, St Jude Children's Hospital, Memphis, TN 38105, USA.
¹⁷ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Surgery, Division of Orthopedic Surgery, McGill University, Montreal, QC H4A 3J1, Canada; Cancer Research Program, RI-MUHC, Montreal, QC H4A 3J1, Canada.
¹⁸ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Surgery, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁹ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
²⁰ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
²¹ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Surgery, University of Toronto, Toronto, ON M5S 1A8, Canada; Texas Children's Cancer and Hematology Center, Houston, TX 77030, USA; Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Texas Children's Hospital, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: mdt.cns@gmail.com.
²² Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: xi.huang@sickkids.ca.

PMID: 39862856
DOI: 10.1016/j.devcel.2025.01.001

A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance

Jerry J Fan et al. Dev Cell. 2025.

. 2025 Jun 9;60(11):1532-1549.e7.

doi: 10.1016/j.devcel.2025.01.001. Epub 2025 Jan 24.

Authors

Affiliations

¹ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
² Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
³ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁴ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
⁵ Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁶ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
⁷ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁸ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Texas Children's Cancer and Hematology Center, Houston, TX 77030, USA; Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, TX 77030, USA.
⁹ Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52246, USA.
¹⁰ Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo 33193, Spain.
¹¹ T-Therapeutics Ltd. One Riverside, Granta Park, Cambridge CB21 6AD, UK.
¹² Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
¹³ Masonic Cancer Center, Department of Pediatrics, and Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
¹⁴ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4Z6, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 2T8, Canada.
¹⁵ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
¹⁶ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Developmental Neurobiology, Neurobiology and Brain Tumor Program, Center of Excellence in Neuro-Oncology Sciences, St Jude Children's Hospital, Memphis, TN 38105, USA.
¹⁷ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Surgery, Division of Orthopedic Surgery, McGill University, Montreal, QC H4A 3J1, Canada; Cancer Research Program, RI-MUHC, Montreal, QC H4A 3J1, Canada.
¹⁸ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Surgery, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁹ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
²⁰ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
²¹ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Surgery, University of Toronto, Toronto, ON M5S 1A8, Canada; Texas Children's Cancer and Hematology Center, Houston, TX 77030, USA; Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Texas Children's Hospital, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: mdt.cns@gmail.com.
²² Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: xi.huang@sickkids.ca.

PMID: 39862856
DOI: 10.1016/j.devcel.2025.01.001

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.

Keywords: KCNB2; functional genomics; insertional mutagenesis; mechanobiology; medulloblastoma; membrane tension; pediatric brain tumor; potassium channel; transposon.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance

Affiliations

A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Research Materials

Miscellaneous