Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression
Abstract Sonic Hedgehog (SHH) medulloblastomas (MBs) exhibit an intermediate prognosis and extensive intertumoral heterogeneity. While SHH pathway antagonists are effective in post-pubertal patients, younger patients exhibit significant side effects, and tumors that harbor mutations in downstream SH...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-09-01
|
| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01646-0 |
| _version_ | 1797453905307631616 |
|---|---|
| author | Stephanie Borlase Alexandria DeCarlo Ludivine Coudière-Morrison Lisa Liang Christopher J. Porter Vijay Ramaswamy Tamra E. Werbowetski-Ogilvie |
| author_facet | Stephanie Borlase Alexandria DeCarlo Ludivine Coudière-Morrison Lisa Liang Christopher J. Porter Vijay Ramaswamy Tamra E. Werbowetski-Ogilvie |
| author_sort | Stephanie Borlase |
| collection | DOAJ |
| description | Abstract Sonic Hedgehog (SHH) medulloblastomas (MBs) exhibit an intermediate prognosis and extensive intertumoral heterogeneity. While SHH pathway antagonists are effective in post-pubertal patients, younger patients exhibit significant side effects, and tumors that harbor mutations in downstream SHH pathway genes will be drug resistant. Thus, novel targeted therapies are needed. Here, we performed preclinical testing of the potent MEK inhibitor (MEKi) trametinib on tumor properties across 2 human and 3 mouse SHH MB models in vitro and in 3 orthotopic MB xenograft models in vivo. Trametinib significantly reduces tumorsphere size, stem/progenitor cell proliferation, viability, and migration. RNA-sequencing on human and mouse trametinib treated cells corroborated these findings with decreased expression of cell cycle, stem cell pathways and SHH-pathway related genes concomitant with increases in genes associated with cell death and ciliopathies. Importantly, trametinib also decreases tumor growth and increases survival in vivo. Cell cycle related E2F target gene sets are significantly enriched for genes that are commonly downregulated in both trametinib treated tumorspheres and primary xenografts. However, IL6/JAK STAT3 and TNFα/NFκB signaling gene sets are specifically upregulated following trametinib treatment in vivo indicative of compensatory molecular changes following long-term MEK inhibition. Our study reveals a novel role for trametinib in effectively attenuating SHH MB tumor progression and warrants further investigation of this potent MEK1/2 inhibitor either alone or in combination with other targeted therapies for the treatment of SHH MB exhibiting elevated MAPK pathway activity. |
| first_indexed | 2024-03-09T15:29:36Z |
| format | Article |
| id | doaj.art-c98e2d8793f44bafba973b7abfd6007f |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-09T15:29:36Z |
| publishDate | 2023-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-c98e2d8793f44bafba973b7abfd6007f2023-11-26T12:21:18ZengNature Publishing GroupCell Death Discovery2058-77162023-09-019111310.1038/s41420-023-01646-0Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progressionStephanie Borlase0Alexandria DeCarlo1Ludivine Coudière-Morrison2Lisa Liang3Christopher J. Porter4Vijay Ramaswamy5Tamra E. Werbowetski-Ogilvie6Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of ManitobaDepartment of Medical Biophysics, University of TorontoDepartment of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of ManitobaDepartment of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of ManitobaOttawa Bioinformatics Core Facility, Ottawa Hospital Research InstituteDepartment of Medical Biophysics, University of TorontoDepartment of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of ManitobaAbstract Sonic Hedgehog (SHH) medulloblastomas (MBs) exhibit an intermediate prognosis and extensive intertumoral heterogeneity. While SHH pathway antagonists are effective in post-pubertal patients, younger patients exhibit significant side effects, and tumors that harbor mutations in downstream SHH pathway genes will be drug resistant. Thus, novel targeted therapies are needed. Here, we performed preclinical testing of the potent MEK inhibitor (MEKi) trametinib on tumor properties across 2 human and 3 mouse SHH MB models in vitro and in 3 orthotopic MB xenograft models in vivo. Trametinib significantly reduces tumorsphere size, stem/progenitor cell proliferation, viability, and migration. RNA-sequencing on human and mouse trametinib treated cells corroborated these findings with decreased expression of cell cycle, stem cell pathways and SHH-pathway related genes concomitant with increases in genes associated with cell death and ciliopathies. Importantly, trametinib also decreases tumor growth and increases survival in vivo. Cell cycle related E2F target gene sets are significantly enriched for genes that are commonly downregulated in both trametinib treated tumorspheres and primary xenografts. However, IL6/JAK STAT3 and TNFα/NFκB signaling gene sets are specifically upregulated following trametinib treatment in vivo indicative of compensatory molecular changes following long-term MEK inhibition. Our study reveals a novel role for trametinib in effectively attenuating SHH MB tumor progression and warrants further investigation of this potent MEK1/2 inhibitor either alone or in combination with other targeted therapies for the treatment of SHH MB exhibiting elevated MAPK pathway activity.https://doi.org/10.1038/s41420-023-01646-0 |
| spellingShingle | Stephanie Borlase Alexandria DeCarlo Ludivine Coudière-Morrison Lisa Liang Christopher J. Porter Vijay Ramaswamy Tamra E. Werbowetski-Ogilvie Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression Cell Death Discovery |
| title | Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression |
| title_full | Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression |
| title_fullStr | Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression |
| title_full_unstemmed | Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression |
| title_short | Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression |
| title_sort | cross species analysis of shh medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression |
| url | https://doi.org/10.1038/s41420-023-01646-0 |
| work_keys_str_mv | AT stephanieborlase crossspeciesanalysisofshhmedulloblastomamodelsrevealssignificantinhibitoryeffectsoftrametinibontumorprogression AT alexandriadecarlo crossspeciesanalysisofshhmedulloblastomamodelsrevealssignificantinhibitoryeffectsoftrametinibontumorprogression AT ludivinecoudieremorrison crossspeciesanalysisofshhmedulloblastomamodelsrevealssignificantinhibitoryeffectsoftrametinibontumorprogression AT lisaliang crossspeciesanalysisofshhmedulloblastomamodelsrevealssignificantinhibitoryeffectsoftrametinibontumorprogression AT christopherjporter crossspeciesanalysisofshhmedulloblastomamodelsrevealssignificantinhibitoryeffectsoftrametinibontumorprogression AT vijayramaswamy crossspeciesanalysisofshhmedulloblastomamodelsrevealssignificantinhibitoryeffectsoftrametinibontumorprogression AT tamraewerbowetskiogilvie crossspeciesanalysisofshhmedulloblastomamodelsrevealssignificantinhibitoryeffectsoftrametinibontumorprogression |