bims-malgli 2024-09-22 papers

Issue of 2024–09–22
five papers selected by
Oltea Sampetrean, Keio University

PNAS Nexus. 2024 Sep;3(9): pgae355

Collagen VI deposition primes the glioblastoma microenvironment for invasion through mechanostimulation of β-catenin signaling.

Junghwa Cha, Erika A Ding, Emily M Carvalho, Annabelle Fowler, Manish K Aghi, Sanjay Kumar.

While glioblastoma (GBM) progression is associated with extensive extracellular matrix (ECM) secretion, the causal contributions of ECM secretion to invasion remain unclear. Here we investigate these contributions by combining engineered materials, proteomics, analysis of patient data, and a model of bevacizumab-resistant GBM. We find that GBM cells cultured in engineered 3D hyaluronic acid hydrogels secrete ECM prior to invasion, particularly in the absence of exogenous ECM ligands. Proteomic measurements reveal extensive secretion of collagen VI, and collagen VI-associated transcripts are correspondingly enriched in microvascular proliferation regions of human GBMs. We further show that bevacizumab-resistant GBM cells deposit more collagen VI than their responsive counterparts, which is associated with marked cell-ECM stiffening. COL6A3 deletion in GBM cells reduces invasion, β-catenin signaling, and expression of mesenchymal markers, and these effects are amplified in hypoxia. Our studies strongly implicate GBM cell-derived collagen VI in microenvironmental remodeling to facilitate invasion.

Keywords: ECM remodeling; ECM stiffening; collagen VI; glioblastoma; hyaluronic acid

DOI: https://doi.org/10.1093/pnasnexus/pgae355

Cancer Res. 2024 Sep 18.

Lipid-laden macrophages recycle myelin to feed glioblastoma.

Lizhi Pang, Fei Zhou, Peiwen Chen.

Tumor-associated microglia and macrophages (TAMs) make up the largest immune cell population in the glioblastoma (GBM) tumor microenvironment (TME). Given the heterogeneity and plasticity of TAMs in the GBM TME, understanding the context-dependent cancer cell-TAM symbiotic interaction is crucial for understanding GBM biology and developing effective therapies. In a recent issue of Cell, Kloosterman and colleagues identified a subpopulation of GPNMBhigh lipid-laden microglia and macrophages (LLMs) in GBM. Mesenchymal-like (MES-like) GBM cells help to generate the LLM phenotype. Reciprocally, LLMs are epigenetically rewired to recycle myelin and transfer the lipid from myelin to cancer cells, fueling MES-like GBM progression in an LXR/ABCA1-dependent manner. Together, leveraging LLMs opens new therapeutic possibilities for rewiring the metabolism-mediated tumor-TAM interaction during GBM progression.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3362

EMBO Rep. 2024 Sep 16.

SOX10 mediates glioblastoma cell-state plasticity.

Ka-Hou Man, Yonghe Wu, Zhenjiang Gao, Anna-Sophie Spreng, Johanna Keding, Jasmin Mangei, Pavle Boskovic, Jan-Philipp Mallm, Hai-Kun Liu, Charles D Imbusch, Peter Lichter, Bernhard Radlwimmer.

Phenotypic plasticity is a cause of glioblastoma therapy failure. We previously showed that suppressing the oligodendrocyte-lineage regulator SOX10 promotes glioblastoma progression. Here, we analyze SOX10-mediated phenotypic plasticity and exploit it for glioblastoma therapy design. We show that low SOX10 expression is linked to neural stem-cell (NSC)-like glioblastoma cell states and is a consequence of temozolomide treatment in animal and cell line models. Single-cell transcriptome profiling of Sox10-KD tumors indicates that Sox10 suppression is sufficient to induce tumor progression to an aggressive NSC/developmental-like phenotype, including a quiescent NSC-like cell population. The quiescent NSC state is induced by temozolomide and Sox10-KD and reduced by Notch pathway inhibition in cell line models. Combination treatment using Notch and HDAC/PI3K inhibitors extends the survival of mice carrying Sox10-KD tumors, validating our experimental therapy approach. In summary, SOX10 suppression mediates glioblastoma progression through NSC/developmental cell-state transition, including the induction of a targetable quiescent NSC state. This work provides a rationale for the design of tumor therapies based on single-cell phenotypic plasticity analysis.

Keywords: SOX10 ; Glioblastoma; Phenotypic Plasticity; Therapy Resistance; Tumor Cell Quiescence

DOI: https://doi.org/10.1038/s44319-024-00258-8

Cold Spring Harb Perspect Biol. 2024 Sep 16. pii: a041373. [Epub ahead of print]

Glial Malignancies.

Suzanne J Baker, Hui Zong, Michelle Monje.

Gliomas comprise a diverse spectrum of related tumor subtypes with varying biological and molecular features and clinical outcomes. Advances in detailed genetic and epigenetic characterizations along with an appreciation that subtypes associated with developmental origins, including brain location and patient age, have shifted glioma classification from the historical reliance on histopathological features to updated categories incorporating molecular signatures and spatiotemporal incidence. Within a subtype, individual gliomas show cellular heterogeneity, generally containing subpopulations resembling different types of normal glial and progenitor cells. In addition to tumor-autonomous mechanisms of aberrant growth regulation driven by genetic mutations and signaling between tumor cells, interactions with the tumor microenvironment, including neurons, astrocytes, oligodendrocyte precursor cells, and the immune microenvironment play important roles in driving glioma growth and influencing response to treatment. The emerging understanding of the complex contributions of normal brain to glioma growth represents new opportunities for therapeutic advances.

DOI: https://doi.org/10.1101/cshperspect.a041373