Abstract
Medulloblastoma (MB) is the most common childhood brain cancer, with Group 3 (G3) as the most aggressive subgroup, being prone to relapse and treatment resistance. A small subset of stem-like cells contributes to this recurrence, but the mechanisms behind their transformation are not fully understood. In this study, we employed therapeutically relevant in vitro and in vivo chemoradiotherapy (CRT) models of G3 MB and discovered a significant activation of SRC kinase following CRT treatment, while other kinases such as AKT and ERK were unaffected. Remarkably, SRC activation was exclusive to G3 MB cells and was absent in the less aggressive Sonic Hedgehog and Group 4 MB, as well as in normal brain cells. SRC activation in CRT-treated G3 MB cell and tumors corresponded with increased stemness, as evidenced by elevated levels of stemness factors SOX2, NOTCH1, OCT4, Nanog and phosphorylated STAT3, alongside a reduction in the differentiation marker βIII-tubulin/TUBB3. Conversely, SRC knockout or pharmacological inhibition promoted differentiation and reduced aggressiveness in CRT-resistant G3 MB cells, which could be rescued by re-expression of SRC in SRC knockout cells. Additionally, SRC inhibition significantly reduced the viability of CRT-treated G3 MB cells by inducing both apoptosis and necroptosis, while sparing the proliferation and stem-like properties of normal neural stem cells, indicating a promising toxicity profile. Importantly, in a therapeutically relevant orthotopic G3 MB model, administration of the re-purposed blood-brain-barrier permeable SRC inhibitor, Saracatinib, in conjunction with CRT, significantly reduced tumor burden and improved animal survival compared to CRT treatment alone without any neurotoxic side effects. Overall, our results underscore the pivotal role of SRC in enhancing stemness and aggressive behavior in CRT-resistant recurrent G3 MB. Targeting SRC not only promotes cell death through apoptosis and necroptosis but also encourages differentiation, positioning it as a promising therapeutic target for rapid clinical interventions.
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Acknowledgements
The authors would like to acknowledge the Central Animal Care Services facilities and staff at the University of Manitoba for their help with animal studies, procedures, and housing. We would like to thank Agnes Fresnoza, Mike Jackson, Rhonda Kelley, Shawn Blum, Chris Taylor, Barry (Dean) Jeske, and Denise Borowski for their help and assistance with the animal work performed in this study. We would like to thank Dr. Jody Haigh and the Cancer Modeling and Imaging Core (CMIC) for providing us with NSG mice from the in-house breeding colony at CancerCare Manitoba for animal studies. We would like to thank Dr. Kirk McManus and Nicole Neudorf for access and assistance using instruments from the QuIPS platform in the Paul Albrechtsen Research Institute at CancerCare Manitoba. TS is supported by operating grants from the Canadian Institutes of Health Research (CIHR) project grant, the Natural Sciences and Engineering Research Council (NSERC), the Canadian Cancer Society (CCS), and the Cancer Research Society (CRS). HK is supported by the Research Manitoba - CancerCare Manitoba PhD Studentship Award. UC is supported by the Rady Faculty of Health Sciences (RFHS) Graduate Studentship. EM is supported by a fellowship from the Brain Tumour Foundation of Canada (BTFC).
Funding
This study was funded by grants from the Canadian Institutes of Health Research (CIHR) project grant, the Natural Sciences and Engineering Research Council (NSERC), the Canadian Cancer Society (CCS), and the Cancer Research Society (CRS).
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Kuzmychova, H., Chawla, U., Martell, E. et al. Targeting SRC enhances differentiation and promotes multifaceted cell death mechanisms in recurrent group 3 medulloblastoma. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08751-9
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DOI: https://doi.org/10.1038/s41419-026-08751-9
