Chronic hypoxia remodels the tumor microenvironment to support glioma stem cell growth.

TitleChronic hypoxia remodels the tumor microenvironment to support glioma stem cell growth.
Publication TypeJournal Article
Year of Publication2024
AuthorsNicholson JG, Cirigliano S, Singhania R, Haywood C, M Dadras S, Yoshimura M, Vanderbilt D, Liechty B, Fine HA
JournalActa Neuropathol Commun
Date Published2024 Mar 25
KeywordsBrain Neoplasms, Cell Line, Tumor, Glioblastoma, Glioma, Humans, Hypoxia, Ligands, Neoplastic Stem Cells, Tumor Microenvironment

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.

Alternate JournalActa Neuropathol Commun
PubMed ID38528608
PubMed Central IDPMC10964514
Grant ListDP1 CA228040 / CA / NCI NIH HHS / United States
DP1-CA228040 / GF / NIH HHS / United States
Related Faculty: 
Benjamin L. Liechty, M.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700