OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma
Abstract Functional cellular heterogeneity in tumours often underlies incomplete response to therapy and relapse. Previously, we demonstrated that the growth of the paediatric brain malignancy, sonic hedgehog subgroup medulloblastoma, is rooted in a dysregulated developmental hierarchy, the apex of...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54858-y |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861804448612352 |
|---|---|
| author | Kinjal Desai Siyi Wanggou Erika Luis Heather Whetstone Chunying Yu Robert J. Vanner Hayden J. Selvadurai Lilian Lee Jinchu Vijay Julia E. Jaramillo Jerry Fan Paul Guilhamon Michelle Kushida Xuejun Li Gregory Stein Santosh Kesari Benjamin D. Simons Xi Huang Peter B. Dirks |
| author_facet | Kinjal Desai Siyi Wanggou Erika Luis Heather Whetstone Chunying Yu Robert J. Vanner Hayden J. Selvadurai Lilian Lee Jinchu Vijay Julia E. Jaramillo Jerry Fan Paul Guilhamon Michelle Kushida Xuejun Li Gregory Stein Santosh Kesari Benjamin D. Simons Xi Huang Peter B. Dirks |
| author_sort | Kinjal Desai |
| collection | DOAJ |
| description | Abstract Functional cellular heterogeneity in tumours often underlies incomplete response to therapy and relapse. Previously, we demonstrated that the growth of the paediatric brain malignancy, sonic hedgehog subgroup medulloblastoma, is rooted in a dysregulated developmental hierarchy, the apex of which is defined by characteristically quiescent SOX2+ stem-like cells. Integrating gene expression and chromatin accessibility patterns in distinct cellular compartments, we identify the transcription factor Olig2 as regulating the stem cell fate transition from quiescence to activation, driving the generation of downstream neoplastic progenitors. Inactivation of Olig2 blocks stem cell activation and tumour output. Targeting this rare OLIG2-driven proliferative programme with a small molecule inhibitor, CT-179, dramatically attenuates early tumour formation and tumour regrowth post-therapy, and significantly increases median survival in vivo. We demonstrate that targeting transition from quiescence to proliferation at the level of the tumorigenic cell could be a pivotal medulloblastoma treatment strategy. |
| format | Article |
| id | doaj-art-583be0ca7399434195b6151e5037f8eb |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-583be0ca7399434195b6151e5037f8eb2025-02-09T12:45:15ZengNature PortfolioNature Communications2041-17232025-02-0116112010.1038/s41467-024-54858-yOLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastomaKinjal Desai0Siyi Wanggou1Erika Luis2Heather Whetstone3Chunying Yu4Robert J. Vanner5Hayden J. Selvadurai6Lilian Lee7Jinchu Vijay8Julia E. Jaramillo9Jerry Fan10Paul Guilhamon11Michelle Kushida12Xuejun Li13Gregory Stein14Santosh Kesari15Benjamin D. Simons16Xi Huang17Peter B. Dirks18Developmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDepartment of Neurosurgery, and Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South UniversityCurtana Pharmaceuticals, IncCurtana Pharmaceuticals, IncDepartment of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of CambridgeDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenDevelopmental and Stem Cell Biology Program, and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenAbstract Functional cellular heterogeneity in tumours often underlies incomplete response to therapy and relapse. Previously, we demonstrated that the growth of the paediatric brain malignancy, sonic hedgehog subgroup medulloblastoma, is rooted in a dysregulated developmental hierarchy, the apex of which is defined by characteristically quiescent SOX2+ stem-like cells. Integrating gene expression and chromatin accessibility patterns in distinct cellular compartments, we identify the transcription factor Olig2 as regulating the stem cell fate transition from quiescence to activation, driving the generation of downstream neoplastic progenitors. Inactivation of Olig2 blocks stem cell activation and tumour output. Targeting this rare OLIG2-driven proliferative programme with a small molecule inhibitor, CT-179, dramatically attenuates early tumour formation and tumour regrowth post-therapy, and significantly increases median survival in vivo. We demonstrate that targeting transition from quiescence to proliferation at the level of the tumorigenic cell could be a pivotal medulloblastoma treatment strategy.https://doi.org/10.1038/s41467-024-54858-y |
| spellingShingle | Kinjal Desai Siyi Wanggou Erika Luis Heather Whetstone Chunying Yu Robert J. Vanner Hayden J. Selvadurai Lilian Lee Jinchu Vijay Julia E. Jaramillo Jerry Fan Paul Guilhamon Michelle Kushida Xuejun Li Gregory Stein Santosh Kesari Benjamin D. Simons Xi Huang Peter B. Dirks OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma Nature Communications |
| title | OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma |
| title_full | OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma |
| title_fullStr | OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma |
| title_full_unstemmed | OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma |
| title_short | OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma |
| title_sort | olig2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma |
| url | https://doi.org/10.1038/s41467-024-54858-y |
| work_keys_str_mv | AT kinjaldesai olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT siyiwanggou olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT erikaluis olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT heatherwhetstone olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT chunyingyu olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT robertjvanner olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT haydenjselvadurai olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT lilianlee olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT jinchuvijay olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT juliaejaramillo olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT jerryfan olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT paulguilhamon olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT michellekushida olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT xuejunli olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT gregorystein olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT santoshkesari olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT benjamindsimons olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT xihuang olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma AT peterbdirks olig2mediatesararetargetablestemcellfatetransitioninsonichedgehogmedulloblastoma |