Visualizing reactive astrogliosis extends survival in glioblastoma patients

Ko, H. Y.; Chung, J.-I.; Kim, D.; Park, Y. M.; Jo, H. H.; Lee, S.; Kim, S. Y.; Kim, J.; Chun, J.-H.; Han, K.-S.; Lee, M.; Ju, Y.; Park, S. J.; Park, K. D.; Nam, M.-H.; Kim, S. H.; Chang, J. H.; Lee, C. J.; Yun, M.

doi:10.1101/2021.04.13.439750

bioRxiv · 10.1101/2021.04.13.439750

Visualizing reactive astrogliosis extends survival in glioblastoma patients

Ko, H. Y.·Chung, J.-I.·Kim, D.·Park, Y. M.·Jo, H. H.·Lee, S.·Kim, S. Y.·Kim, J.·Chun, J.-H.·Han, K.-S.·Lee, M.·Ju, Y.·Park, S. J.·Park, K. D.·Nam, M.-H.·Kim, S. H.·Chang, J. H.·Lee, C. J.·Yun, M.

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Abstract

Glioblastoma multiforme (GBM) is a devastating brain tumor with dismal prognosis of only 15-month survival regardless of surgical resection. Here, we report an advanced neuroimaging technique combining 11C-acetate PET and MRI (AcePET), visualizing the boundary beyond the MRI-defined tumor. Targeted biopsy of the regions with increased 11C-acetate uptake revealed the presence of reactive astrocytes with enhanced acetate-transporter MCT1, along with cancer stem cells. Reactive astrogliosis and MCT1-dependent 11C-acetate-uptake were recapitulated in U87MG-orthotopic models. Mechanistically, glycolytic tumor cells release excessive acetate causing reactive astrogliosis, leading to the release of aberrant astrocytic GABA and H2O2, which further down-regulate the neuronal glucose uptake through GLUT3. Clincally, AcePET-guided surgery allows complete tumor resection of infiltrating cancer stem cells and extends the overall survival of patients by 5.25 months compared to conventional MRI-guided surgery. We established a new concept of the metabolic interactions between GBM cells and neighboring neurons through reactive astrocytes and developed AcePET-guided surgery to fight against GBM.

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Ko, H. Y., Chung, J.-I., Kim, D., Park, Y. M., Jo, H. H., Lee, S., Kim, S. Y., Kim, J., Chun, J.-H., Han, K.-S., Lee, M., Ju, Y., Park, S. J., Park, K. D., Nam, M.-H., Kim, S. H., Chang, J. H., Lee, C. J., Yun, M.. 2021-04-14. Visualizing reactive astrogliosis extends survival in glioblastoma patients. https://doi.org/10.1101/2021.04.13.439750

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