bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–04–20
twelve papers selected by
Oltea Sampetrean, Keio University
  1. Reprogramming the tumor immune microenvironment to treat glioblastoma.
  2. Discovery and therapeutic exploitation of Master Regulatory miRNAs in Glioblastoma.
  3. The excitatory milieu in glioma: mechanisms and therapeutic avenues.
  4. An oncohistone-driven H3.3K27M/CREB5/ID1 axis maintains the stemness and malignancy of diffuse intrinsic pontine glioma.
  5. The novel brain penetrant ATM inhibitor WSD0628 provides robust radiosensitization of brain tumor patient derived xenografts.
  6. Precancerous Cells Initiate Glioblastoma Evolution and Contribute to Intratumoral Heterogeneity.
  7. High peritumoral network connectedness in glioblastoma reveals a distinct epigenetic signature and is associated with decreased overall survival.
  8. Mapping the spatial architecture of glioblastoma from core to edge delineates niche-specific tumor cell states and intercellular interactions.
  9. A Spatial Multi-Omic Framework Identifies Gliomas Permissive to TIL Expansion.
  10. Overcoming myeloid-driven resistance to CAR T therapy by targeting SPP1.
  11. IL-7-mediated expansion of autologous lymphocytes increases CD8+ VLA-4 expression and accumulation in glioblastoma models.
  12. Exploring the Microbiome's Impact on Glioma and Brain Metastases: Insights into Development, Progression, and Treatment Response-A Scoping Review.
  1. Nat Med. 2025 Apr;31(4): 1048-1049
    Reprogramming the tumor immune microenvironment to treat glioblastoma.
    Johanna A Joyce.
      
    DOI:  https://doi.org/10.1038/s41591-025-03636-4
  2. bioRxiv. 2025 Apr 03. pii: 2025.04.01.646663. [Epub ahead of print]
    Discovery and therapeutic exploitation of Master Regulatory miRNAs in Glioblastoma.
    Shekhar Saha, Ying Zhang, Myron K Gilbert, Collin Dube, Farina Hanif, Elizabeth Qian Xu Mulcahy, Sylwia Bednarek, Pawel Marcinkiewicz, Xiantao Wang, Gijung Kwak, Kadie Hudson, Yunan Sun, Manikarna Dinda, Tapas Saha, Fadila Guessous, Nichola Cruickshanks, Rossymar Rivera Colon, Lily Dell'Olio, Rajitha Anbu, Benjamin Kefas, Pankaj Kumar, Alexander L Klibanov, David Schiff, Jung Soo Suk, Justin Hanes, Jamie Mata, Markus Hafner, Roger Abounader.
      Glioblastoma is a fatal primary malignant brain tumor. Despite therapies involving surgical resection, chemotherapy, and radiation therapy, the average survival for glioblastoma patients remains at approximately 15 months. MicroRNAs (miRNAs) are short noncoding RNA molecules that regulate the expression of the majority of human genes. Numerous genes are concurrently deregulated in glioblastoma. Consequently, molecular monotherapies have failed to achieve improvements in clinical outcomes. Several lines of evidence suggest that simultaneous targeting of several deregulated molecules is required to achieve better therapies. However, the simultaneous targeting of several deregulated oncogenic drivers is severely limited by the fact that the drugs needed to target many deregulated molecules do not currently exist, and because combining several drugs in a clinical setting leads to an exponential increase in toxicity. We hypothesized that we can develop and use miRNA to simultaneously inhibit multiple deregulated genes for more efficacious glioblastoma therapies. The goal of this study was therefore to identify master regulatory microRNAs (miRNAs) and use them to simultaneously target multiple deregulated molecules for GBM therapy. We defined master regulatory miRNAs as those that target several deregulated genes in glioblastoma. To find master regulatory miRNAs, we first used PAR-CLIP screenings to identify all targets of all miRNAs in glioblastoma cells. We then analyzed TCGA tumor data to determine which of these targets are deregulated in human tumors. We developed and used an algorithm to rank these targets for significance in glioblastoma malignancy based on their magnitude of deregulation, frequency of deregulation, and correlation with patient survival. We then ranked the miRNAs for their capacity of targeting multiple glioblastoma-deregulated genes and therefore the potential to exhibit strong anti-tumor effects when delivered as therapy. Using this strategy, we selected two tumor suppressor master regulatory miRNAs, miR-340, miR-382 and an oncogenic master regulatory miRNA, miR-17. We validated the target genes of the miRNAs and showed that they form part of important glioblastoma regulatory pathways. We then showed that the miRNAs (miR-340 and miR-582) or the miR-17 inhibitor have strong inhibitory effects on glioblastoma cell growth, survival, invasion, stemness and in vivo tumor growth. Ultimately, we developed and successfully tested a new therapeutic approach to delivery miR-340 using MRI guided focused ultrasound and microbubbles (FUS-MB) and special brain penetrating nanoparticles (BPN). This approach resulted in a substantial reduction in tumor volume and prolongation of the survival of glioblastoma-bearing mice and can be translated into clinical trials. We therefore developed and successfully tested a novel strategy to discover and deliver miRNAs for glioblastoma and cancer therapy.
    One Sentence Summary: We developed and used new computational, experimental, and therapeutic approaches to identify and therapeutically deliver master regulatory miRNAs to inhibit the growth of glioblastoma, the most common and deadly primary brain tumor.
    DOI:  https://doi.org/10.1101/2025.04.01.646663
  3. Neuro Oncol. 2025 Apr 18. pii: noaf063. [Epub ahead of print]
    The excitatory milieu in glioma: mechanisms and therapeutic avenues.
    Bobak F Khalili, Karan Dixit, David O Kamson, Craig Horbinski, Delilah J Przybyla, Matthew C Tate, Amy B Heimberger, Rimas V Lukas, Jessica W Templer.
      Gliomas are the most common primary malignant brain tumors. Their electrobiologic properties drive disease development, and in select tumors, aberrant neurosignaling is situated at the crux of gliomagenesis and glioma-related epilepsy (GRE). Tumor microtubes and the neuronal-glioma synapse are defined components of the glioma circuitry. The nidus of cortical hyperexcitability-the peri-glioma-undergoes severe alterations during disease progression and is influenced by genetic mutations, anomalous synaptic remodeling, inflammatory changes and an imbalance in neurotransmitters. Such pathologic mechanisms have been exploited for anticancer and antiseizure value wherein a subset remain to be explored. In this Review, we discuss the hyperexcitable conditions within the glioma microenvironment and candidate therapies for seizure and tumor control.
    Keywords:  Epilepsy; Glioma; Glioma microenvironment; Glioma-related epilepsy; Peritumoral hyperexcitability
    DOI:  https://doi.org/10.1093/neuonc/noaf063
  4. Nat Commun. 2025 Apr 17. 16(1): 3675
    An oncohistone-driven H3.3K27M/CREB5/ID1 axis maintains the stemness and malignancy of diffuse intrinsic pontine glioma.
    Wei Zhou, Cheng Xu, Shuangrui Yang, Haocheng Li, Changcun Pan, Zhuang Jiang, Luyang Xie, Xiaohan Li, Huimin Qiao, Da Mi, Yujie Tang, Liwei Zhang, Qiaoran Xi.
      Diffuse intrinsic pontine glioma (DIPG), a lethal pediatric cancer driven by H3K27M oncohistones, exhibits aberrant epigenetic regulation and stem-like cell states. Here, we uncover an axis involving H3.3K27M oncohistones, CREB5/ID1, which sustains the stem-like state of DIPG cells, promoting malignancy. We demonstrate that CREB5 mediates elevated ID1 levels in the H3.3K27M/ACVR1WT subtype, promoting tumor growth; while BMP signaling regulates this process in the H3.1K27M/ACVR1MUT subtype. Furthermore, we reveal that H3.3K27M directly enhances CREB5 expression by reshaping the H3K27me3 landscape at the CREB5 locus, particularly at super-enhancer regions. Additionally, we elucidate the collaboration between CREB5 and BRG1, the SWI/SNF chromatin remodeling complex catalytic subunit, in driving oncogenic transcriptional changes in H3.3K27M DIPG. Intriguingly, disrupting CREB5 super-enhancers with ABBV-075 significantly reduces its expression and inhibits H3.3K27M DIPG tumor growth. Combined treatment with ABBV-075 and a BRG1 inhibitor presents a promising therapeutic strategy for clinical translation in H3.3K27M DIPG treatment.
    DOI:  https://doi.org/10.1038/s41467-025-58795-2
  5. Neuro Oncol. 2025 Apr 15. pii: noaf102. [Epub ahead of print]
    The novel brain penetrant ATM inhibitor WSD0628 provides robust radiosensitization of brain tumor patient derived xenografts.
    Zhiyi Xue, Ann C Mladek, Sneha Rathi, Sonia Jain, Rachael A Vaubel, Lateef A Odukoya, Darwin A Garcia, Lily Liu, Katrina K Bakken, Brett L Carlson, Lauren L Ott, Danielle M Burgenske, Zeng Hu, Sonja Dragojevic, Paul A Decker, Matthew L Kosel, William G Breen, Shiv K Gupta, Jeanette E Eckel-Passow, William F Elmquist, Wei Zhong, Jann N Sarkaria.
       BACKGROUND: The ataxia telangiectasia mutated (ATM) protein coordinates the cellular response to therapeutic radiation, and ATM inhibitors can potentially enhance the efficacy of radiation in otherwise radiation-resistant tumors.
    METHODS: The small molecule ATM kinase inhibitor WSD0628 was specifically designed for enhanced distribution across the blood brain barrier to more effectively treat glioblastoma (GBM) and brain metastases in combination with radiation therapy (RT). GBM and brain metastasis patient-derived xenograft (PDX) models were used to understand target inhibition, radiosensitization, inhibition of the DNA damage response, and in vivo efficacy.
    RESULTS: Initial in vitro characterization of WSD0628 demonstrate a high-level of selectivity across kinase families, limited aldehyde oxidase liability, and low risk of hERG interactions. Consistent with a central role for ATM in radiation response, WSD0628 blocked radiation-induced signaling and enhanced radiosensitivity in U251 glioma cells and brain tumor PDXs GBM120 and M12. In comparison to control or RT alone in orthotopic PDXs, the combination of WSD0628 with RT markedly prolonged median survival - GBM12 (19, 55 and 408 days, respectively); GBM43 (26, 44 and 143 days, respectively); GBM120 (51, 89 and 231 days, respectively); M12 (17, 39 and 190 days, respectively). Pharmacokinetic and pharmacodynamic testing after treatment in orthotopic GBM43 tumors showed inhibitory levels of WSD0628 and a reduction of γH2AX foci in the combination-treated tumors.
    CONCLUSION: Collectively, these results suggest a promising role for WSD0628 in combination with RT in brain tumors and provide the rationale for an ongoing Phase 0/1A clinical trial testing this combination in recurrent GBM.
    Keywords:  ATM inhibition; DNA Damage; GBM PDX; Radiosensitization; WSD0628
    DOI:  https://doi.org/10.1093/neuonc/noaf102
  6. Cancer Discov. 2025 Apr 16.
    Precancerous Cells Initiate Glioblastoma Evolution and Contribute to Intratumoral Heterogeneity.
    Hyun Jung Kim, Keon Woo Kim, Do Hyeon Cha, Jihwan Yoo, Eui Hyun Kim, Jong Hee Chang, Seok-Gu Kang, Jung Won Park, Ja Hye Kim, Yeonhee Lee, Eunha Lim, Yiseul Kim, Myeong Heui Kim, Xue Li, Joo Ho Lee, Jeong Ho Lee.
      Neural stem cells (NSCs) in the subventricular zone (SVZ) are identified as cells-of-origin harboring driver mutations in glioblastoma (GBM), which is the most devastating brain tumor with highly heterogeneous nature. However, the sequential transformation of a limited number of mutation-harboring NSCs into a distant tumor with high intratumoral heterogeneity remains poorly understood. In this study, we have identified transcriptionally distinct types of mutation-harboring precancerous cells in our spontaneous, somatic mouse model recapitulating human GBM evolution as well as in tumor-free SVZ tissues from patients. These precancerous cells emerge via oligodendrocyte lineage specification, exhibiting unique transcriptional programs involving dysregulated translations and extracellular matrix remodeling. Subsequently, they give rise to heterogeneous tumor cell populations by activating multiple programs crucial for gliomagenesis. Our findings highlight the pivotal role of precancerous cells in tumor evolution and intratumoral heterogeneity, suggesting their potential as a novel therapeutic target for GBM.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0234
  7. Neuro Oncol. 2025 Apr 15. pii: noaf101. [Epub ahead of print]
    High peritumoral network connectedness in glioblastoma reveals a distinct epigenetic signature and is associated with decreased overall survival.
    Kerstin Jütten, Jonas Ort, Julius M Kernbach, Anke Meyer-Baese, Uwe Meyer-Baese, Hussam Aldin Hamou, Hans Clusmann, Martin Wiesmann, Juliane Bremer, Henner Koch, Aniella Bak, Franz Ricklefs, Richard Drexler, Dieter-Henrik Heiland, Daniel Delev.
       BACKGROUND: Glioblastomas are functionally integrated into their peritumoral neural environment, and the dynamic functional interaction can be analyzed using network theory, providing insights into the tumor-brain interface. We investigated peritumoral network connectedness of glioblastomas, revealing its association with distinct epigenetic signatures, its influence on survival, and its susceptibility to modification through surgical treatment.
    METHODS: Resting-state fMRI was performed on 48 glioblastoma patients. Tumor lesions were segmented, and networks were constructed at 10mm and 40mm distances from the tumor margin. These networks were mirrored to the healthy hemisphere to compare lesional and contralesional networks. The difference between lesional and contralesional mean degree centrality was calculated to assess peritumoral network connectedness. Its correlation with epigenetic signatures and effect on overall survival were analyzed. Surgery-induced changes in peritumoral network connectedness were evaluated in seven patients with follow-up data.
    RESULTS: Mean degree centrality was significantly higher in the lesional compared to the contralesional network (p=.032), indicating a tumor-induced effect on its local environment and reflecting high peritumoral network connectedness. Glioblastomas with a neural high epigenetic signature exhibited increased peritumoral network connectedness (p=.010), which was associated with decreased survival (p=.036). Postoperative peritumoral network connectedness tended to decrease, suggesting that surgical resection disrupts the functional communication between the tumor and its peritumoral environment.
    CONCLUSIONS: The role of network features in predicting patient survival suggests their clinical relevance as imaging biomarkers for assessing personalized treatment strategies, which may include targeting crucial nodes for disconnection or even neuromodulation of neural circuits.
    Keywords:  Glioblastoma; degree centrality; network theory; overall survival; resting-state functional connectivity
    DOI:  https://doi.org/10.1093/neuonc/noaf101
  8. bioRxiv. 2025 Apr 04. pii: 2025.04.04.647096. [Epub ahead of print]
    Mapping the spatial architecture of glioblastoma from core to edge delineates niche-specific tumor cell states and intercellular interactions.
    Saad M Khan, Anthony Z Wang, Rupen R Desai, Colin R McCornack, Rui Sun, Sonika M Dahiya, Jennifer Foltz-Stringfellow, Ngima D Sherpa, Lydia Leavitt, Timothy West, Alexander F Wang, Aleksandar Krbanjevic, Bryan D Choi, Eric C Leuthardt, Bhuvic Patel, Al Charest, Albert H Kim, Gavin P Dunn, Allegra A Petti.
      Treatment resistance in glioblastoma (GBM) is largely driven by the extensive multi-level heterogeneity that typifies this disease. Despite significant progress toward elucidating GBM's genomic and transcriptional heterogeneity, a critical knowledge gap remains in defining this heterogeneity at the spatial level. To address this, we employed spatial transcriptomics to map the architecture of the GBM ecosystem. This revealed tumor cell states that are jointly defined by gene expression and spatial localization, and multicellular niches whose composition varies along the tumor core-edge axis. Ligand-receptor interaction analysis uncovered a complex network of intercellular communication, including niche- and region-specific interactions. Finally, we found that CD8 \J GZMK \J T cells colocalize with LYVE1 \J CD163 \J myeloid cells in vascular regions, suggesting a potential mechanism for immune evasion. These findings provide novel insights into the GBM tumor microenvironment, highlighting previously unrecognized patterns of spatial organization and intercellular interactions, and novel therapeutic avenues to disrupt tumor-promoting interactions and overcome immune resistance.
    DOI:  https://doi.org/10.1101/2025.04.04.647096
  9. bioRxiv. 2025 Apr 12. pii: 2025.03.26.645566. [Epub ahead of print]
    A Spatial Multi-Omic Framework Identifies Gliomas Permissive to TIL Expansion.
    Kelly M Hotchkiss, Kenan Zhang, Anna M Corcoran, Elizabeth Owens, Pamela Noldner, Chelsea Railton, Kyra Van Batavia, Ying Zhou, Jodie Jepson, Kirit Singh, Roger McLendon, Kristen Batich, Anoop P Patel, Katayoun Ayasoufi, Michael C Brown, Evan Calabrese, Jichun Xie, Jose Conejo-Garcia, Beth H Shaz, John W Hickey, Mustafa Khasraw.
      Tumor-infiltrating lymphocyte (TIL) therapy, recently approved by the FDA for melanoma, is an emerging modality for cell-based immunotherapy. However, its application in immunologically 'cold' tumors such as glioblastoma remains limited due to sparse T cell infiltration, antigenic heterogeneity, and a suppressive tumor microenvironment. To identify genomic and spatial determinants of TIL expandability, we performed integrated, multimodal profiling of high-grade gliomas using spectral flow cytometry, TCR sequencing, single-cell RNA-seq, Xenium in situ transcriptomics, and CODEX spatial proteomics. Comparative analysis of TIL-generating (TIL+) versus non-generating (TIL-) tumors revealed that IL7R expression, structured perivascular immune clustering, and tumor-intrinsic metabolic programs such as ACSS3 were associated with successful TIL expansion. In contrast, TIL-; tumors were enriched for neuronal lineage signatures, immunosuppressive transcripts including TOX and FERMT1, and tumor-connected macrophages. This study defines spatial and molecular correlates of TIL manufacturing success and establishes a genomics-enabled selection platform for adoptive T cell therapy. The profiling approach is now being prospectively implemented in the GIANT clinical trial ( NCT06816927 ), supporting its translational relevance and scalability across glioblastoma and other immune-excluded cancers.
    DOI:  https://doi.org/10.1101/2025.03.26.645566
  10. bioRxiv. 2025 Apr 03. pii: 2025.04.01.646202. [Epub ahead of print]
    Overcoming myeloid-driven resistance to CAR T therapy by targeting SPP1.
    Sharareh Gholamin, Heini M Natri, Yuqi Zhao, Shengchao Xu, Maryam Aftabizadeh, Begonya Comin-Anduix, Supraja Saravanakumar, Christian Masia, Robyn A Wong, Lance Peter, Mei-I Chung, Evan D Mee, Brenda Aguilar, Renate Starr, Davis Y Torrejon, Darya Alizadeh, Xiwei Wu, Anusha Kalbasi, Antoni Ribas, Stephen Forman, Behnam Badie, Nicholas E Banovich, Christine E Brown.
      Chimeric antigen receptor (CAR) T cell therapy faces notable limitations in treatment of solid tumors. The suppressive tumor microenvironment (TME), characterized by complex interactions among immune and stromal cells, is gaining recognition in conferring resistance to CAR T cell therapy. Despite the abundance and diversity of macrophages in the TME, their intricate involvement in modulating responses to CAR T cell therapies remains poorly understood. Here, we conducted single-cell RNA sequencing (scRNA-seq) on tumors from 41 glioma patients undergoing IL13Rα2-targeted CAR T cell therapy, identifying elevated suppressive SPP1 signatures predominantly in macrophages from patients who were resistant to treatment. Further integrative scRNA-seq analysis of high-grade gliomas as well as an interferon-signaling deficient syngeneic mouse model-both resistant to CAR T therapy-demonstrated the role of congruent suppressive pathways in mediating resistance to CAR T cells and a dominant role for SPP1+ macrophages. SPP1 blockade with an anti-SPP1 antibody abrogates the suppressive TME effects and substantially prolongs survival in IFN signaling-deficient and glioma syngeneic mouse models resistant to CAR T cell therapy. These findings illuminate the role of SPP1+ macrophages in fueling a suppressive TME and driving solid tumor resistance to CAR cell therapies. Targeting SPP1 may serve as a universal strategy to reprogram immune dynamics in solid tumors mitigating resistance to CAR T therapies.
    DOI:  https://doi.org/10.1101/2025.04.01.646202
  11. J Clin Invest. 2025 Apr 17. pii: e181471. [Epub ahead of print]
    IL-7-mediated expansion of autologous lymphocytes increases CD8+ VLA-4 expression and accumulation in glioblastoma models.
    Kirit Singh, Kelly M Hotchkiss, Sarah L Cook, Pamy Noldner, Ying Zhou, Eliese M Moelker, Chelsea O Railton, Emily E Blandford, Bhairavy J Puviindran, Shannon E Wallace, Pamela K Norberg, Gary E Archer, Beth H Shaz, Katayoun Ayasoufi, John H Sampson, Mustafa Khasraw, Peter E Fecci.
      The efficacy of T cell-activating therapies against glioma is limited by an immunosuppressive tumor microenvironment and tumor-induced T cell sequestration. We investigated whether peripherally infused non-antigen specific autologous lymphocytes (ALT) could accumulate in intracranial tumors. We observed that non-specific autologous CD8+ ALT cells can indeed accumulate in this context, despite endogenous T cell sequestration in bone marrow. Rates of intratumoral accumulation were markedly increased when expanding lymphocytes with IL-7 compared to IL-2. Pre-treatment with IL-7 ALT also enhanced the efficacy of multiple tumor-specific and non-tumor-specific T cell-dependent immunotherapies against orthotopic murine and human xenograft gliomas. Mechanistically, we detected increased VLA-4 on mouse and human CD8+ T cells following IL-7 expansion, with increased transcription of genes associated with migratory integrin expression (CD9). We also observed that IL-7 increases S1PR1 transcription in human CD8+ T cells, which we have shown to be protective against tumor-induced T cell sequestration. These observations demonstrate that expansion with IL-7 enhances the capacity of ALT to accumulate within intracranial tumors, and that pre-treatment with IL-7 ALT can boost the efficacy of subsequent T cell-activating therapies against glioma. Our findings will inform the development of future clinical trials where ALT pre-treatment can be combined with T cell-activating therapies.
    Keywords:  Cell migration/adhesion; Immunotherapy; Neuroscience; Oncology; T cells
    DOI:  https://doi.org/10.1172/JCI181471
  12. Cancers (Basel). 2025 Apr 04. pii: 1228. [Epub ahead of print]17(7):
    Exploring the Microbiome's Impact on Glioma and Brain Metastases: Insights into Development, Progression, and Treatment Response-A Scoping Review.
    Jennifer Leigh, Becky Skidmore, Adrian Wong, Saman Maleki Vareki, Terry L Ng.
      Background: The human microbiome plays a crucial role in health and disease. Dysbiosis, an imbalance of microorganisms, has been implicated in cancer development and treatment response, including in primary brain tumors and brain metastases, through interactions mediated by the gut-brain axis. This scoping review synthesizes current evidence on the relationship between the human microbiome and brain tumors. Methods: A systematic search of five electronic databases was conducted by an expert librarian, using controlled vocabulary and keywords. A targeted grey literature search in Google Scholar and clinical trial registries was also undertaken. Eligible studies included primary research involving human patients, or in vivo, or in vitro models of glioma or brain metastasis, with a focus on the microbiome's role in tumor development, treatment response, and outcomes. Results: Out of 584 citations screened, 40 studies met inclusion criteria, comprising 24 articles and 16 conference abstracts. These included 12 human studies, 16 using mouse models, 7 combining both, and 5 employing large datasets or next-generation sequencing of tumor samples. Thirty-one studies focused on primary brain tumors, six on brain metastases, and three on both. Of the 20 studies examining dysbiosis in tumor development, 95% (n = 19) found an association with tumor growth. Additionally, 71.4% (n = 5/7) of studies reported that microbiome alterations influenced treatment efficacy. Conclusions: Although the role of the gut-brain axis in brain tumors is still emerging and is characterized by heterogeneity across studies, existing evidence consistently supports a relationship between the gut microbiome and both brain tumor development and treatment outcomes.
    Keywords:  brain tumor; brain–gut axis; dysbiosis; glioblastoma; glioma; microbiome
    DOI:  https://doi.org/10.3390/cancers17071228
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