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Chronic hypoxia remodels the tumor microenvironment to support glioma stem cell growth.
Nicholson, J G; Cirigliano, S; Singhania, R; Haywood, C; Shahidi Dadras, M; Yoshimura, M; Vanderbilt, D; Liechty, B; Fine, H A.
Afiliación
  • Nicholson JG; Department of Neurology, Weill Cornell Medicine, New York, NY, USA.
  • Cirigliano S; Department of Neurology, Weill Cornell Medicine, New York, NY, USA.
  • Singhania R; Department of Neurology, Weill Cornell Medicine, New York, NY, USA.
  • Haywood C; Department of Neurology, Weill Cornell Medicine, New York, NY, USA.
  • Shahidi Dadras M; Department of Neurology, Weill Cornell Medicine, New York, NY, USA.
  • Yoshimura M; Department of Neurology, Weill Cornell Medicine, New York, NY, USA.
  • Vanderbilt D; Department of Neurology, Weill Cornell Medicine, New York, NY, USA.
  • Liechty B; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine/New York-Presbyterian Hospital, New York, NY, USA.
  • Fine HA; Department of Neurology, Weill Cornell Medicine, New York, NY, USA. haf9016@med.cornell.edu.
Acta Neuropathol Commun ; 12(1): 46, 2024 Mar 25.
Article en En | MEDLINE | ID: mdl-38528608
ABSTRACT
Cerebral organoids co-cultured with patient derived glioma stem cells (GLICOs) are an experimentally tractable research tool useful for investigating the role of the human brain tumor microenvironment in glioblastoma. Here we describe long-term GLICOs, a novel model in which COs are grown from embryonic stem cell cultures containing low levels of GSCs and tumor development is monitored over extended durations (ltGLICOs). Single-cell profiling of ltGLICOs revealed an unexpectedly long latency period prior to GSC expansion, and that normal organoid development was unimpaired by the presence of low numbers of GSCs. However, as organoids age they experience chronic hypoxia and oxidative stress which remodels the tumor microenvironment to promote GSC expansion. Receptor-ligand modelling identified astrocytes, which secreted various pro-tumorigenic ligands including FGF1, as the primary cell type for GSC crosstalk and single-cell multi-omic analysis revealed these astrocytes were under the control of ischemic regulatory networks. Functional validation confirmed hypoxia as a driver of pro-tumorigenic astrocytic ligand secretion and that GSC expansion was accelerated by pharmacological induction of oxidative stress. When controlled for genotype, the close association between glioma aggressiveness and patient age has very few proposed biological explanations. Our findings indicate that age-associated increases in cerebral vascular insufficiency and associated regional chronic cerebral hypoxia may contribute to this phenomenon.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Glioblastoma / Glioma Límite: Humans Idioma: En Revista: Acta Neuropathol Commun Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Glioblastoma / Glioma Límite: Humans Idioma: En Revista: Acta Neuropathol Commun Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido