bims-malgli 2023-07-02 papers

Acta Neuropathol Commun. 2023 Jun 24. 11(1): 104

On the origin and development of glioblastoma: multifaceted role of perivascular mesenchymal stromal cells.

F Ah-Pine, M Khettab, Y Bedoui, Y Slama, M Daniel, B Doray, P Gasque.

Glioblastoma, IDH wild-type is the most common and aggressive form of glial tumors. The exact mechanisms of glioblastoma oncogenesis, including the identification of the glioma-initiating cell, are yet to be discovered. Recent studies have led to the hypothesis that glioblastoma arises from neural stem cells and glial precursor cells and that cell lineage constitutes a key determinant of the glioblastoma molecular subtype. These findings brought significant advancement to the comprehension of gliomagenesis. However, the cellular origin of glioblastoma with mesenchymal molecular features remains elusive. Mesenchymal stromal cells emerge as potential glioblastoma-initiating cells, especially with regard to the mesenchymal molecular subtype. These fibroblast-like cells, which derive from the neural crest and reside in the perivascular niche, may underlie gliomagenesis and exert pro-tumoral effects within the tumor microenvironment. This review synthesizes the potential roles of mesenchymal stromal cells in the context of glioblastoma and provides novel research avenues to better understand this lethal disease.

Keywords: Glioblastoma; Gliomagenesis; Mesenchymal stromal cells; Microenvironment; Neural crest; Pericytes; Perivascular fibroblasts

DOI: https://doi.org/10.1186/s40478-023-01605-x

Nature. 2023 Jun 28.

Remote neuronal activity drives glioma progression through SEMA4F.

The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity-dependent infiltrating population present at the leading edge of mouse and human tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity.

DOI: https://doi.org/10.1038/s41586-023-06267-2

Cancer Discov. 2023 Jun 28. pii: CD-22-0869. [Epub ahead of print]

Sex-biased T cell exhaustion drives differential immune responses in glioblastoma.

Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunological sex differences are not fully understood. Here, we demonstrate T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD1 treatment. Moreover, increased T cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by X chromosome inactivation escape gene Kdm6a. These findings demonstrate sex-biased pre-determined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0869

Sci Adv. 2023 Jun 28. 9(26): eadf7170

Scale-free correlations and potential criticality in weakly ordered populations of brain cancer cells.

Kevin B Wood, Andrea Comba, Sebastien Motsch, Tomás S Grigera, Pedro R Lowenstein.

Collective behavior spans several orders of magnitude of biological organization, from cell colonies to flocks of birds. We used time-resolved tracking of individual glioblastoma cells to investigate collective motion in an ex vivo model of glioblastoma. At the population level, glioblastoma cells display weakly polarized motion in the (directional) velocities of single cells. Unexpectedly, fluctuations in velocities are correlated over distances many times the size of a cell. Correlation lengths scale linearly with the maximum end-to-end length of the population, indicating that they are scale-free and lack a characteristic decay scale other than the size of the system. Last, a data-driven maximum entropy model captures statistical features of the experimental data with only two free parameters: the effective length scale (nc) and strength (J) of local pairwise interactions between tumor cells. These results show that glioblastoma assemblies exhibit scale-free correlations in the absence of polarization, suggesting that they may be poised near a critical point.

DOI: https://doi.org/10.1126/sciadv.adf7170

Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad074

Temporally modulated pulsed proton re-irradiation (TMPPR) for recurrent high-grade gliomas.

Alonso La Rosa, Alonso N Gutierrez, Yazmin Odia, Michael W McDermott, Manmeet S Ahluwalia, Minesh P Mehta, Rupesh Kotecha.

DOI: https://doi.org/10.1093/noajnl/vdad074

Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad065

Deep proteome investigation of high-grade gliomas reveals heterogeneity driving differential metabolism of 5-aminolevulinic acid.

Saicharan Ghantasala, Amruth Bhat, Unnati Agarwal, Deeptarup Biswas, Prawesh Bhattarai, Sridhar Epari, Aliasgar Moiyadi, Sanjeeva Srivastava.

Background: Fluorescence-guided surgery (FGS) using 5-aminolevulinic acid (5-ALA) as adjunct for high-grade gliomas (HGGs) has been on the rise in recent years. Despite being largely effective, we observed multiple histologically similar sub-regions of the same tumor from a few individuals with varying protoporphyrin IX (PpIX) levels. The current study aims at understanding the proteomic changes driving differential metabolism of 5-ALA in HGGs.Methods: Biopsies were histologically and biochemically assayed. Following this, a deep proteomics investigation was carried out using high resolution liquid chromatography-mass spectrometry (HR LC-MS) to identify protein expression in differentially fluorescing regions of HGGs.
Results: Our analysis identified 5437 proteins with high confidence. Differential analysis in the subgroup with HGGs carrying IDH mutation (IDH mt.) revealed 93 differentially regulated proteins (raw p-value ≤ 0.05 and absolute FC ≥ 1.5). Similar analysis in the IDH wild type (IDH wt.) subgroup revealed 20 differentially regulated proteins. Gene set enrichment analysis (GSEA) identified key pathways like ion channel transport, trafficking of AMPA receptors, and regulation of heme-oxygenase-1 in the IDH wt. subgroup. Pathways such as scavenging of heme, signaling by NOTCH4, negative regulation of PI3-AKT pathway, and iron uptake and transport were observed to be differentially regulated in the IDH mt. subgroup.
Conclusions: Tumor regions from the same patient exhibiting differential fluorescence following 5-ALA administration were observed to have different proteome profiles. Future studies aimed at a better molecular understanding of 5-ALA metabolism in HGGs hold the potential to increase the efficacy of FGS and the use of 5-ALA as a theragnostic tool.

Keywords: 5-ALA; GSEA; HR LC–MS; deep proteome; heme biosynthesis

DOI: https://doi.org/10.1093/noajnl/vdad065