Glioma synapses recruit mechanisms of adaptive plasticity

被引：4

作者：

Taylor, Kathryn R. ^{[1
]}

Barron, Tara ^{[1
]}

Hui, Alexa ^{[1
]}

Spitzer, Avishay ^{[2
]}

Yalcin, Belgin ^{[1
]}

Ivec, Alexis E. ^{[1
]}

Geraghty, Anna C. ^{[1
]}

Hartmann, Griffin G. ^{[1
]}

Arzt, Marlene ^{[1
]}

Gillespie, Shawn M. ^{[1
]}

Kim, Yoon Seok ^{[1
]}

Jahan, Samin Maleki ^{[1
]}

Zhang, Helena ^{[1
]}

Shamardani, Kiarash ^{[1
]}

Su, Minhui ^{[1
]}

Ni, Lijun ^{[1
]}

Du, Peter P. ^{[1
]}

Woo, Pamelyn J. ^{[1
]}

Silva-Torres, Arianna ^{[1
]}

Venkatesh, Humsa S. ^{[1
]}

Mancusi, Rebecca ^{[1
]}

Ponnuswami, Anitha ^{[1
]}

Mulinyawe, Sara ^{[1
]}

Keough, Michael B. ^{[1
]}

Chau, Isabelle ^{[1
]}

Aziz-Bose, Razina ^{[1
]}

Tirosh, Itay ^{[2
]}

Suva, Mario L. ^{[3
,4
,5
,6
]}

Monje, Michelle ^{[1
,7
,8
,9
,10
]}

机构：

[1] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[2] Weizmann Inst Sci, Dept Mol Cell Biol, Rehovot, Israel

[3] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[4] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA

[5] Harvard Med Sch, Boston, MA 02115 USA

[6] Broad Inst MIT & Harvard, Boston, MA USA

[7] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA

[8] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[9] Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA

[10] Stanford Calif, Howard Hughes Med Inst, Stanford, CA 94305 USA

来源：

NATURE | 2023年 / 623卷 / 7986期

关键词：

LONG-TERM POTENTIATION; AMPA RECEPTOR TRAFFICKING; POSITIVE SOLID TUMORS; SYNAPTIC-TRANSMISSION; NEUROTROPHIC FACTOR; GLUTAMATE RECEPTORS; EXPRESSION; LTP; TRKB; CELL;

D O I：

10.1038/d41586-023-03275-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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) receptors(4,5). The consequent glioma cell membrane depolarization drives tumour proliferation(4,6). In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity(7,8) and strength(9-15). Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B-16 (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 plasticity(17-22) that contributes to memory and learning in the healthy brain(23-26). 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.

引用

页码：366 / +

页数：33

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