bims-malgli 2023-11-05 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2023–11–05
six papers selected by
Oltea Sampetrean, Keio University

Glioma synapses recruit mechanisms of adaptive plasticity.
Quantitative analysis of MGMT promoter methylation in glioblastoma suggests nonlinear prognostic effect.
Interactions between ploidy and resource availability shape clonal interference at initiation and recurrence of glioblastoma.
Variant allelic frequencies of driver mutations can identify gliomas with potentially false-negative MGMT promoter methylation results.
Tumor Volume Growth Rates and Doubling Times during Active Surveillance of IDH-mutant Low-Grade Glioma.
The STEMRI trial: Magnetic resonance spectroscopy imaging can define tumor areas enriched in glioblastoma stem-like cells.

Nature. 2023 Nov 01.

Glioma synapses recruit mechanisms of adaptive plasticity.

Kathryn R Taylor, Tara Barron, Alexa Hui, Avishay Spitzer, Belgin Yalçin, Alexis E Ivec, Anna C Geraghty, Griffin G Hartmann, Marlene Arzt, Shawn M Gillespie, Yoon Seok Kim, Samin Maleki Jahan, Helena Zhang, Kiarash Shamardani, Minhui Su, Lijun Ni, Peter P Du, Pamelyn J Woo, Arianna Silva-Torres, Humsa S Venkatesh, Rebecca Mancusi, Anitha Ponnuswami, Sara Mulinyawe, Michael B Keough, Isabelle Chau, Razina Aziz-Bose, Itay Tirosh, Mario L Suvà, Michelle Monje.

The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor1-3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors4,5. The consequent glioma cell membrane depolarization drives tumour proliferation4,6. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity7,8 and strength9-15. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity17-22 that contributes to memory and learning in the healthy brain23-26. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.

DOI: https://doi.org/10.1038/s41586-023-06678-1
Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad115

Quantitative analysis of MGMT promoter methylation in glioblastoma suggests nonlinear prognostic effect.

David Gibson, Akshay Ravi, Eduardo Rodriguez, Susan Chang, Nancy Oberheim Bush, Jennie Taylor, Jennifer Clarke, David Solomon, Aaron Scheffler, John Witte, Hannah Lambing, Hideho Okada, Mitchel Berger, Farid Chehab, Nicholas A Butowski.

   Background: Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative methods of measuring promoter methylation, providing clearer insight into its functional relationship with survival.
Methods: A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point, MGMT promoter methylation index. GBMs of 240 newly diagnosed patients were sequenced and risk for mortality was assessed. Nonlinearities were captured by fitting splines to Cox proportional hazard models and plotting smoothed residuals. Covariates included age, Karnofsky performance status, IDH1 mutation, and extent of resection.
Results: Median follow-up time and progression-free survival were 16 and 9 months, respectively. A total of 176 subjects experienced death. A one-unit increase in promoter CpG methylation resulted in a 4% reduction in hazard (95% CI 0.93-0.99, P < .005). GBM patients with low levels of promoter methylation (1-6 CpG sites) fared markedly worse (HR = 1.62, 95% CI 1.03-2.54, P < .036) than individuals who were unmethylated. Subjects with medium levels of promoter methylation (7-12 sites) had the greatest reduction in hazard (HR = 0.48, 95% CI 0.29-0.80, P < .004), followed by individuals in the highest promoter methylation tertile (HR = 0.62, 95% CI 0.40-0.97, P < .035).
Conclusions: Our findings suggest that the relationship between the extent of MGMT promoter methylation and survival in GBM may be nonlinear. These findings challenge the current understanding of MGMT and underlines the clinical importance of determining its prognostic utility. Potential limitations include censoring, sample size, and extraneous mutations.

Keywords:  CpG; MGMT; bisulfite sequencing; glioblastoma; methylation

DOI:  https://doi.org/10.1093/noajnl/vdad115
bioRxiv. 2023 Oct 20. pii: 2023.10.17.562670. [Epub ahead of print]

Interactions between ploidy and resource availability shape clonal interference at initiation and recurrence of glioblastoma.

Zuzanna Nowicka, Frederika Rentzeperis, Richard Beck, Vural Tagal, Ana Forero Pinto, Elisa Scanu, Thomas Veith, Jackson Cole, Didem Ilter, William Dominguez Viqueira, Jamie K Teer, Konstantin Maksin, Stefano Pasetto, Mahmoud A Abdalah, Giada Fiandaca, Sandhya Prabhakaran, Andrew Schultz, Maureiq Ojwang, Jill S Barnholtz-Sloan, Joaquim M Farinhas, Ana P Gomes, Parag Katira, Noemi Andor.

Glioblastoma (GBM) is the most aggressive form of primary brain tumor. Complete surgical resection of GBM is almost impossible due to the infiltrative nature of the cancer. While no evidence for recent selection events have been found after diagnosis, the selective forces that govern gliomagenesis are strong, shaping the tumor's cell composition during the initial progression to malignancy with late consequences for invasiveness and therapy response. We present a mathematical model that simulates the growth and invasion of a glioma, given its ploidy level and the nature of its brain tissue micro-environment (TME), and use it to make inferences about GBM initiation and response to standard-of-care treatment. We approximate the spatial distribution of resource access in the TME through integration of in-silico modelling, multi-omics data and image analysis of primary and recurrent GBM. In the pre-malignant setting, our in-silico results suggest that low ploidy cancer cells are more resistant to starvation-induced cell death. In the malignant setting, between first and second surgery, simulated tumors with different ploidy compositions progressed at different rates. Whether higher ploidy predicted fast recurrence, however, depended on the TME. Historical data supports this dependence on TME resources, as shown by a significant correlation between the median glucose uptake rates in human tissues and the median ploidy of cancer types that arise in the respective tissues (Spearman r = -0.70; P = 0.026). Taken together our findings suggest that availability of metabolic substrates in the TME drives different cell fate decisions for cancer cells with different ploidy and shapes GBM disease initiation and relapse characteristics.

DOI: https://doi.org/10.1101/2023.10.17.562670
Acta Neuropathol Commun. 2023 Nov 02. 11(1): 175

Variant allelic frequencies of driver mutations can identify gliomas with potentially false-negative MGMT promoter methylation results.

Matthew McCord, Pouya Jamshidi, Vineeth Thirunavu, Lucas Santana-Santos, Erica Vormittag-Nocito, David Dittman, Stephanie Parker, Joseph Baczkowski, Lawrence Jennings, Jordain Walshon, Kathleen McCortney, Kristyn Galbraith, Hui Zhang, Rimas V Lukas, Roger Stupp, Karan Dixit, Priya Kumthekar, Amy B Heimberger, Matija Snuderl, Craig Horbinski.

  MGMT promoter methylation testing is required for prognosis and predicting temozolomide response in gliomas. Accurate results depend on sufficient tumor cellularity, but histologic estimates of cellularity are subjective. We sought to determine whether driver mutation variant allelic frequency (VAF) could serve as a more objective metric for cellularity and identify possible false-negative MGMT samples. Among 691 adult-type diffuse gliomas, MGMT promoter methylation was assessed by pyrosequencing (N = 445) or DNA methylation array (N = 246); VAFs of TERT and IDH driver mutations were assessed by next generation sequencing. MGMT results were analyzed in relation to VAF. By pyrosequencing, 56% of all gliomas with driver mutation VAF ≥ 0.325 had MGMT promoter methylation, versus only 37% with VAF < 0.325 (p < 0.0001). The mean MGMT promoter pyrosequencing score was 19.3% for samples with VAF VAF ≥ 0.325, versus 12.7% for samples with VAF < 0.325 (p < 0.0001). Optimal VAF cutoffs differed among glioma subtypes (IDH wildtype glioblastoma: 0.12-0.18, IDH mutant astrocytoma: ~0.33, IDH mutant and 1p/19q co-deleted oligodendroglioma: 0.3-0.4). Methylation array was more sensitive for MGMT promoter methylation at lower VAFs than pyrosequencing. Microscopic examination tended to overestimate tumor cellularity when VAF was low. Re-testing low-VAF cases with methylation array and droplet digital PCR (ddPCR) confirmed that a subset of them had originally been false-negative. We conclude that driver mutation VAF is a useful quality assurance metric when evaluating MGMT promoter methylation tests, as it can help identify possible false-negative cases.

Keywords:  Glioma; MGMT promoter; Methylation; Temozolomide; Variant allelic frequency

DOI:  https://doi.org/10.1186/s40478-023-01680-0
Clin Cancer Res. 2023 Nov 01.

Tumor Volume Growth Rates and Doubling Times during Active Surveillance of IDH-mutant Low-Grade Glioma.

Ankush Bhatia, Raquel Moreno, Anne S Reiner, Subhiksha Nandakumar, Henry S Walch, Teena M Thomas, Philip J Nicklin, Ye Choi, Anna Skakodub, Rachna Malani, Vivek Prabhakaran, Pallavi Tiwari, Maria Diaz, Katherine S Panageas, Ingo K Mellinghoff, Tejus A Bale, Robert J Young.

PURPOSE: Isocitrate-dehydrogenase-mutant (IDH-mt) gliomas are incurable primary brain tumors characterized by a slow-growing phase over several years followed by a rapid-growing malignant phase. We hypothesized that tumor volume growth rate (TVGR) on magnetic resonance imaging may act as an earlier measure of clinical benefit during the active surveillance period.
EXPERIMENTAL DESIGN: We integrated 3-dimensional volumetric measurements with clinical, radiological, and molecular data in a retrospective cohort of IDH-mt gliomas that were observed after surgical resection in order to understand tumor growth kinetics and the impact of molecular genetics.
RESULTS: Using log-linear mixed modeling, the entire cohort (n=128) had a continuous %TVGR per 6 months of 10.46% (95% CI: [9.11%, 11.83%]) and a doubling time of 3.5 years (95% CI: [3.10-3.98]). High molecular grade IDH-mt gliomas, defined by the presence of homozygous deletion of CDKN2A/B, had %TVGR per 6 months of 19.17% (95% CI: [15.57%, 22.89%]) which was significantly different from low molecular grade IDH-mt gliomas with a growth rate per 6 months of 9.54% (95% CI: [7.32%, 11.80%]) (P < 0.0001). Using joint modeling to co-model the longitudinal course of TVGR and overall survival, we found each one natural logarithm tumor volume increase resulted in more than a 3-fold increase in risk of death (HR=3.83, 95% CI: [2.32-6.30], P < 0.0001).
CONCLUSIONS: TVGR may be used as an earlier measure of clinical benefit and correlates well with the WHO 2021 molecular classification of gliomas and survival. Incorporation of TVGR as a surrogate endpoint into future prospective studies of IDH-mt gliomas may accelerate drug development.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-1180
Sci Adv. 2023 Nov 03. 9(44): eadi0114

The STEMRI trial: Magnetic resonance spectroscopy imaging can define tumor areas enriched in glioblastoma stem-like cells.

Anthony Lemarié, Vincent Lubrano, Caroline Delmas, Amélie Lusque, Juan-Pablo Cerapio, Marion Perrier, Aurore Siegfried, Florent Arnauduc, Yvan Nicaise, Perrine Dahan, Thomas Filleron, Muriel Mounier, Christine Toulas, Elizabeth Cohen-Jonathan Moyal.

Despite maximally safe resection of the magnetic resonance imaging (MRI)-defined contrast-enhanced (CE) central tumor area and chemoradiotherapy, most patients with glioblastoma (GBM) relapse within a year in peritumoral FLAIR regions. Magnetic resonance spectroscopy imaging (MRSI) can discriminate metabolic tumor areas with higher recurrence potential as CNI+ regions (choline/N-acetyl-aspartate index >2) can predict relapse sites. As relapses are mainly imputed to glioblastoma stem-like cells (GSCs), CNI+ areas might be GSC enriched. In this prospective trial, 16 patients with GBM underwent MRSI/MRI before surgery/chemoradiotherapy to investigate GSC content in CNI-/+ biopsies from CE/FLAIR. Biopsy and derived-GSC characterization revealed a FLAIR/CNI+ sample enrichment in GSC and in gene signatures related to stemness, DNA repair, adhesion/migration, and mitochondrial bioenergetics. FLAIR/CNI+ samples generate GSC-enriched neurospheres faster than FLAIR/CNI-. Parameters assessing biopsy GSC content and time-to-neurosphere formation in FLAIR/CNI+ were associated with worse patient outcome. Preoperative MRI/MRSI would certainly allow better resection and targeting of FLAIR/CNI+ areas, as their GSC enrichment can predict worse outcomes.

DOI: https://doi.org/10.1126/sciadv.adi0114