Glioblastoma remodelling of human neural circuits decreases survival

Saritha Krishna, Abrar Choudhury, Michael B. Keough, Kyounghee Seo, Lijun Ni, Sofia Kakaizada, Anthony Lee, Alexander Aabedi, Galina Popova, Benjamin Lipkin, Caroline Cao, Cesar Nava Gonzales, Rasika Sudharshan, Andrew Egladyous, Nyle Almeida, Yalan Zhang, Annette M. Molinaro, Humsa S. Venkatesh, Andy G. S. Daniel, Kiarash Shamardani, Jeanette Hyer, Edward F. Chang, Anne Findlay, Joanna J. Phillips, Shawn L. Hervey-Jumper 

Nature volume 617, pages599–607 (2023) DOIhttps://doi.org/10.1038/s41586-023-06036-1

 Abstract

Gliomas synaptically integrate into neural circuits1^,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1^,2^,3^,4 and gliomas increasing neuronal excitability2^,5^,6^,7^,8. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron–glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.

ig. 1 | High-grade gliomas remodel long-range functional neural circuits

·         교종은 뉴런과 시냅스 수준으로 연결되어 뇌 회로에 통합됨

·         종양은 정상보다 더 넓은 뇌 영역의 기능적 회로를 재구성함

·         기능적 연결성이 높은 종양 부위에는→ 시냅스 형성·뉴런 성장 촉진 성질을 가진 교모세포종 아형이 존재

·         이 종양 세포들은 thrombospondin-1을 분비

·         가바펜틴으로 thrombospondin-1을 억제하면 종양 증식 감소

·         종양–뇌 기능적 연결성이 높을수록 생존율과 언어 인지 기능이 나쁨

👉 결론: 고등급 교종은 뇌 신경 회로를 재편성해 종양 성장을 촉진하고, 동시에 인지 기능을 손상시킨다.