bims-malgli 2025-01-05 papers

Nat Commun. 2025 Jan 02. 16(1): 272

Invasion of glioma cells through confined space requires membrane tension regulation and mechano-electrical coupling via Plexin-B2.

Chrystian Junqueira Alves, Theodore Hannah, Sita Sadia, Christy Kolsteeg, Angela Dixon, Robert J Wiener, Ha Nguyen, Murray J Tipping, Júlia Silva Ladeira, Paula Fernandes da Costa Franklin, Nathália de Paula Dutra de Nigro, Rodrigo Alves Dias, Priscila V Zabala Capriles, José P Rodrigues Furtado de Mendonça, Paul A Slesinger, Kevin D Costa, Hongyan Zou, Roland H Friedel.

Glioblastoma (GBM) is a malignant brain tumor with diffuse infiltration. Here, we demonstrate how GBM cells usurp guidance receptor Plexin-B2 for confined migration through restricted space. Using live-cell imaging to track GBM cells negotiating microchannels, we reveal endocytic vesicle accumulation at cell front and filamentous actin assembly at cell rear in a polarized manner. These processes are interconnected and require Plexin-B2 signaling. We further show that Plexin-B2 governs membrane tension and other membrane features such as endocytosis, phospholipid composition, and inner leaflet surface charge, thus providing biophysical mechanisms by which Plexin-B2 promotes GBM invasion. Together, our studies unveil how GBM cells regulate membrane tension and mechano-electrical coupling to adapt to physical constraints and achieve polarized confined migration.

DOI: https://doi.org/10.1038/s41467-024-55056-6

Neuro Oncol. 2025 Jan 02. pii: noae275. [Epub ahead of print]

Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide.

BACKGROUND: Temozolomide (TMZ) treatment has demonstrated, but variable, impact on glioma prognosis. This study examines associations of survival with DNA repair gene germline polymorphisms among glioma patients who did and did not have TMZ treatment. Identifying genetic markers which sensitize tumor cells to TMZ could personalize therapy and improve outcomes.
METHODS: We evaluated TMZ-related survival associations of pathogenic germline SNPs and genetically predicted transcript levels within 34 DNA repair genes among 1504 glioma patients from the UCSF Adult Glioma Study and Mayo Clinic whose diagnoses spanned pre- and post-TMZ eras within the major known glioma prognostic molecular subtypes.
RESULTS: Among those who received TMZ, 5 SNPs were associated with overall survival, but not in those who did not receive TMZ. Only rs2308321-G, in MGMT, was associated with decreased survival (HR=1.21, p=0.019) for all glioma subtypes. Rs73191162-T (near UNG), rs13076508-C (near PARP3), rs7840433-A (near NEIL2), and rs3130618-A (near MSH5) were only associated with survival and TMZ treatment for certain subtypes, suggesting subtype-specific germline chemo-sensitization.Genetically predicted elevated compared to normal brain expression of PNKP was associated with dramatically worse survival for TMZ-treated patients with IDH-mutant and 1p/19q non-codeleted gliomas (p=0.015), with a median difference of over 70 months in overall survival times. Similarly, NEIL2 and TDG expressions were associated with altered TMZ-related survival only among certain subtypes.
CONCLUSIONS: Functional germline alterations within DNA repair genes were associated with TMZ sensitivity, measured by overall survival, among adults with glioma, these variants should be evaluated in prospective analyses and functional studies.

Keywords: DNA damage repair; glioma; pharmacogenomics; survival; temozolomide

DOI: https://doi.org/10.1093/neuonc/noae275

Nat Commun. 2024 Dec 30. 15(1): 10757

Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort.

Glioblastoma is immunologically "cold" and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we enrolled an additional 25 patients with a primary endpoint of evaluating the cell cycle gene signature associated with neoadjuvant pembrolizumab and performed bulk-RNA seq on resected tumor tissue (NCT02852655). Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent positive risk factor for survival. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not confirm a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma and our secondary endpoint of PFS-6 was 19.5% (95% CI: 9.29-41.2%) for the pooled neoadjuvant cohorts. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively.

DOI: https://doi.org/10.1038/s41467-024-54326-7

Nat Commun. 2024 Dec 30. 15(1): 10885

Turning attention to tumor-host interface and focus on the peritumoral heterogeneity of glioblastoma.

Fang Wang, Jiawei Dong, Yuyun Xu, Jiaqi Jin, Yan Xu, Xiuwei Yan, Zhihui Liu, Hongtao Zhao, Jiheng Zhang, Nan Wang, Xueyan Hu, Xin Gao, Lei Xu, Chengyun Yang, Shuai Ma, Jianyang Du, Ying Hu, Hang Ji, Shaoshan Hu.

Approximately 90% of glioblastoma recurrences occur in the peritumoral brain zone (PBZ), while the spatial heterogeneity of the PBZ is not well studied. In this study, two PBZ tissues and one tumor tissue sample are obtained from each patient via preoperative imaging. We assess the microenvironment and the characteristics of infiltrating immune/tumor cells using various techniques. Our data indicate there are one or more regions with higher cerebral blood flow in PBZ, which we collectively name the "higher cerebral blood flow interface" (HBI). The HBI exhibited more neovascularization than the "lower cerebral blood flow interfaces" (LBI). The HBI tend to have increased infiltration of macrophages and T lymphocytes infiltration compared with that in LBI. There are more tumor cells in the HBI than in LBI, with substantial differences in the gene expression profiles of these tumor cells. HBI may be the key area of PBZ-targeting therapy after surgical resection.

DOI: https://doi.org/10.1038/s41467-024-55243-5

Nat Commun. 2025 Jan 02. 16(1): 340

Multiparametric MRI along with machine learning predicts prognosis and treatment response in pediatric low-grade glioma.

Pediatric low-grade gliomas (pLGGs) exhibit heterogeneous prognoses and variable responses to treatment, leading to tumor progression and adverse outcomes in cases where complete resection is unachievable. Early prediction of treatment responsiveness and suitability for immunotherapy has the potential to improve clinical management and outcomes. Here, we present a radiogenomic analysis of pLGGs, integrating MRI and RNA sequencing data. We identify three immunologically distinct clusters, with one group characterized by increased immune activity and poorer prognosis, indicating potential benefit from immunotherapies. We develop a radiomic signature that predicts these immune profiles with over 80% accuracy. Furthermore, our clinicoradiomic model predicts progression-free survival and correlates with treatment response. We also identify genetic variants and transcriptomic pathways associated with progression risk, highlighting links to tumor growth and immune response. This radiogenomic study in pLGGs provides a framework for the identification of high-risk patients who may benefit from targeted therapies.

DOI: https://doi.org/10.1038/s41467-024-55659-z