Minhui Su

All Publications

• GABAergic neuron-to-glioma synapses in diffuse midline gliomas. Nature Barron, T., Yalçın, B., Su, M., Byun, Y. G., Gavish, A., Shamardani, K., Xu, H., Ni, L., Soni, N., Mehta, V., Maleki Jahan, S., Kim, Y. S., Taylor, K. R., Keough, M. B., Quezada, M. A., Geraghty, A. C., Mancusi, R., Vo, L. T., Castañeda, E. H., Woo, P. J., Petritsch, C. K., Vogel, H., Kaila, K., Monje, M. 2025

  Abstract

  High-grade gliomas (HGGs) are the leading cause of brain cancer-related death. HGGs include clinically, anatomically and molecularly distinct subtypes that stratify into diffuse midline gliomas (DMGs), such as H3K27M-altered diffuse intrinsic pontine glioma, and hemispheric HGGs, such as IDH wild-type glioblastoma. Neuronal activity drives glioma progression through paracrine signalling1,2 and neuron-to-glioma synapses3-6. Glutamatergic AMPA receptor-dependent synapses between neurons and glioma cells have been demonstrated in paediatric3 and adult4 high-grade gliomas, and early work has suggested heterogeneous glioma GABAergic responses7. However, neuron-to-glioma synapses mediated by neurotransmitters other than glutamate remain understudied. Using whole-cell patch-clamp electrophysiology, in vivo optogenetics and patient-derived orthotopic xenograft models, we identified functional, tumour-promoting GABAergic neuron-to-glioma synapses mediated by GABAA receptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 chloride transporter function and consequently elevated intracellular chloride concentration in DMG malignant cells. As membrane depolarization increases glioma proliferation3,6, we found that the activity of GABAergic interneurons promotes DMG proliferation in vivo. The benzodiazepine lorazepam enhances GABA-mediated signalling, increases glioma proliferation and growth, and shortens survival in DMG patient-derived orthotopic xenograft models. By contrast, only minimal depolarizing GABAergic currents were found in hemispheric HGGs and lorazepam did not influence the growth rate of hemispheric glioblastoma xenografts. Together, these findings uncover growth-promoting GABAergic synaptic communication between GABAergic neurons and H3K27M-altered DMG cells, underscoring a tumour subtype-specific mechanism of brain cancer neurophysiology.

  View details for DOI 10.1038/s41586-024-08579-3

  View details for PubMedID 39972132

  View details for PubMedCentralID 4447122

• Glioma synapses recruit mechanisms of adaptive plasticity. Nature Taylor, K. R., Barron, T., Hui, A., Spitzer, A., Yalcin, B., Ivec, A. E., Geraghty, A. C., Hartmann, G. G., Arzt, M., Gillespie, S. M., Kim, Y. S., Maleki Jahan, S., Zhang, H., Shamardani, K., Su, M., Ni, L., Du, P. P., Woo, P. J., Silva-Torres, A., Venkatesh, H. S., Mancusi, R., Ponnuswami, A., Mulinyawe, S., Keough, M. B., Chau, I., Aziz-Bose, R., Tirosh, I., Suva, M. L., Monje, M. 2023

  Abstract

  The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor1-3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors4,5. The consequent glioma cell membrane depolarization drives tumour proliferation4,6. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity7,8 and strength9-15. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity17-22 that contributes to memory and learning in the healthy brain23-26. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.

  View details for DOI 10.1038/s41586-023-06678-1

  View details for PubMedID 37914930

• An optimized quantitative proteomics method establishes the cell type-resolved mouse brain secretome EMBO JOURNAL Tueshaus, J., Mueller, S. A., Kataka, E., Zaucha, J., Sebastian Monasor, L., Su, M., Guener, G., Jocher, G., Tahirovic, S., Frishman, D., Simons, M., Lichtenthaler, S. F. 2020; 39 (20): e105693

  Abstract

  To understand how cells communicate in the nervous system, it is essential to define their secretome, which is challenging for primary cells because of large cell numbers being required. Here, we miniaturized secretome analysis by developing the "high-performance secretome protein enrichment with click sugars" (hiSPECS) method. To demonstrate its broad utility, hiSPECS was used to identify the secretory response of brain slices upon LPS-induced neuroinflammation and to establish the cell type-resolved mouse brain secretome resource using primary astrocytes, microglia, neurons, and oligodendrocytes. This resource allowed mapping the cellular origin of CSF proteins and revealed that an unexpectedly high number of secreted proteins in vitro and in vivo are proteolytically cleaved membrane protein ectodomains. Two examples are neuronally secreted ADAM22 and CD200, which we identified as substrates of the Alzheimer-linked protease BACE1. hiSPECS and the brain secretome resource can be widely exploited to systematically study protein secretion and brain function and to identify cell type-specific biomarkers for CNS diseases.

  View details for DOI 10.15252/embj.2020105693

  View details for Web of Science ID 000571191100001

  View details for PubMedID 32954517

  View details for PubMedCentralID PMC7560198