bims-malgli 2024-08-04 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2024–08–04
eleven papers selected by
Oltea Sampetrean, Keio University

Correction for Kudruk et al., Multimodal neuro-nanotechnology: Challenging the existing paradigm in glioblastoma therapy.
Low level of tumor necrosis factor α in tumor microenvironment maintains self-renewal of glioma stem cells by Vasorin-mediated glycolysis.
A comparative analysis of IDH-mutant glioma in pediatric, young adult, and older adult patients.
Targeting Catechol-O-Methyltransferase Induces Mitochondrial Dysfunction and Enhances the Efficacy of Radiotherapy in Glioma.
γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner.
GDNF/GFRA1 signaling contributes to chemo- and radioresistance in glioblastoma.
Cranioencephalic functional lymphoid units in glioblastoma.
Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells.
Glioblastoma Neurovascular Progenitor Orchestrates Tumor Cell Type Diversity.
Dual targeting of histone deacetylases and MYC as potential treatment strategy for H3-K27M pediatric gliomas.
Diffuse, IDH-wildtype gliomas in adults with minimal histological change and isolated TERT promoter mutation: not simply CNS WHO grade 4.

Proc Natl Acad Sci U S A. 2024 Aug 06. 121(32): e2413733121

Correction for Kudruk et al., Multimodal neuro-nanotechnology: Challenging the existing paradigm in glioblastoma therapy.

DOI: https://doi.org/10.1073/pnas.2413733121
Neuro Oncol. 2024 Aug 02. pii: noae147. [Epub ahead of print]

Low level of tumor necrosis factor α in tumor microenvironment maintains self-renewal of glioma stem cells by Vasorin-mediated glycolysis.

Yang Zhang, Tianxu Kang, Yuxi Wang, Chao Song, Huan Li, Hailong Mi, Yachao Li, Minhai Dong, Xiaoyu Ma, Hongtao Zhu, Lidong Cheng, Po Zhang, Zhiye Chen, Lin Zhou, Qiulian Wu, Feng Mao, Baofeng Wang, Suojun Zhang, Kai Shu, Feng Wan, Wenchao Zhou, Jeremy N Rich, Jianying Shen, Qungen Xiao, Xingjiang Yu.

   BACKGROUND: Self-renewal of glioma stem cells (GSCs) is responsible for glioblastoma (GBM) therapy-resistant and recurrence. Tumor necrosis factor α (TNFα) and TNF signaling pathway display an antitumor activity in preclinical models and in tumor patients. However, TNFα exhibits no significance for glioma clinical prognosis based on Glioma Genome Atlas database. This study aimed to explore whether TNFα of tumor microenvironment maintains self-renewal of GSCs and promotes worse prognosis in glioma patient.
METHODS: Spatial transcriptomics, immunoblotting, sphere formation assay, extreme limiting dilution, and gene expression analysis were used to determine the role of TNFα on GSC's self-renewal. Mass spectrometry, RNA-sequencing detection, bioinformatic analyses, qRT-RNA, immunofluorescence, immunohistochemistry, single cell RNA sequencing, in vitro and in vivo models were used to uncover the mechanism of TNFα-induced GSC self-renewal.
RESULTS: Low level of TNFα displays a promoting effect on GSC self-renewal and worse glioma prognosis. Mechanistically, Vasorin (VASN) mediated TNFα-induced self-renewal by potentiating glycolysis. Lactate produced by glycolysis inhibits the TNFα secretion of tumor-associated macrophages (TAMs) and maintains TNFα in a low level.
CONCLUSIONS: TNFα-induced GSC self-renewal mediated by VASN provides a possible explanation for the failures of endogenous TNFα effect on GBM. Combination of targeting VASN and TNFα anti-tumor effect may be an effective approach for treating GBM.

Keywords:  Glioma stem cell; Glycolysis; Tumor necrosis factor α; Tumor-associated macrophages

DOI:  https://doi.org/10.1093/neuonc/noae147
Neuro Oncol. 2024 Jul 31. pii: noae142. [Epub ahead of print]

A comparative analysis of IDH-mutant glioma in pediatric, young adult, and older adult patients.

Mary Jane Lim-Fat, Jennifer A Cotter, Mehdi Touat, Jayne Vogelzang, Cecilia Sousa, Will Pisano, Jack Geduldig, Varun Bhave, Joseph Driver, Pei-Chi Kao, Alana McGovern, Clement Ma, Ashley S Margol, Kristina Cole, Amy Smith, Stewart Goldman, Kristiyana Kaneva, Ai Lien Truong, Kellie J Nazemi, Matthew D Wood, Karen D Wright, Wendy B London, Katherine E Warren, Patrick Y Wen, Wenya Linda Bi, Sanda Alexandrescu, David A Reardon, Keith L Ligon, Kee Kiat Yeo.

BACKGROUND: The frequency and significance of IDH mutations in glioma across age groups is incompletely understood. We performed a multi-center retrospective age-stratified comparison of patients with IDH-mutant gliomas to identify age-specific differences in clinico-genomic features, treatments, and outcomes.
METHODS: Clinical, histologic, and sequencing data from patients with IDH-mutant, grade 2-4 gliomas, were collected from collaborating institutions between 2013-2019. Patients were categorized as pediatric (<19y), YA (19-39y) or older adult (≥40y). Clinical presentation, treatment, histologic, and molecular features were compared across age categories using Fisher's exact test or analysis-of-variance. Cox proportional-hazards regression was used to determine association of age and other covariates with overall (OS) and progression-free survival (PFS).
RESULTS: We identified a cohort of 379 patients (204 YA) with IDH-mutant glioma with clinical data. There were 155 (41%) oligodendrogliomas and 224 (59%) astrocytomas. YA showed significantly shorter PFS and shorter median time-to-malignant transformation (MT) compared to pediatric and adult groups, but no significant OS difference. Adjusting for pathology type, extent of resection, and upfront therapy in multivariable analysis, the YA group was independently prognostic of shorter PFS than pediatric and adult groups. Among astrocytomas, CDK4/6 copy number amplifications were associated with both shorter PFS and shorter OS. Among oligodendrogliomas, PIK3CA and CDKN2A/2B alterations were associated with shorter OS.
CONCLUSIONS: IDH-mutant glioma YA patients had significantly shorter PFS and time to MT but did not differ in OS compared to pediatric and adult groups. Treatment approach varied significantly by patient age and warrant further study as addressable age-associated outcome drivers.

DOI: https://doi.org/10.1093/neuonc/noae142
Cancer Res. 2024 Aug 01.

Targeting Catechol-O-Methyltransferase Induces Mitochondrial Dysfunction and Enhances the Efficacy of Radiotherapy in Glioma.

Meng Jiao, Christopher J Pirozzi, Chen Yu, Xuhui Bao, Mengjie Hu, Dong Pan, Sejiro Littleton, Nathan Reynolds, Daniel R Saban, Fang Li, Chuan-Yuan Li.

Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation. Here, we assessed the role of catechol-o-methyltransferase (COMT), a key enzyme to degrade catecholamines and a drug target for Parkinson's disease, in glioma treatment. Analysis of TCGA data showed significantly higher COMT expression levels in both low-grade glioma and glioblastoma compared to normal brain tissues. Inhibition of COMT by genetic knockout or FDA-approved COMT inhibitors significantly sensitized glioma cells to RT in vitro and in vivo. Mechanistically, COMT inhibition in glioma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral double-stranded RNA sensing pathway and type I interferon (IFN) response. Elevated type I IFNs stimulated the phagocytic capacity of microglial cells, enhancing RT efficacy. Given the long-established safety record of the COMT inhibitors, these findings provide a solid rationale to evaluate them in combination with RT in glioma patients.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0134
bioRxiv. 2024 Jul 22. pii: 2024.07.18.603996. [Epub ahead of print]

γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner.

Asmita Pathak, Sravya Palasalava, Maxon V Knott, Bruno Colon, Erika Ciervo, Yadi Zhou, Jonathan Mitchell, Oriana Teran Pumar, Harrison K A Wong, Li Zhang, Nikola Susic, Khushi Hemendra Shah, Kristen Kay, Diana Chin, Sadie Johnson, Feixiong Cheng, Costas A Lyssiotis, Dionysios C Watson, Michele Ceccarelli, Ashish Shah, Daniel R Wahl, Justin D Lathia, Defne Bayik.

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.

DOI: https://doi.org/10.1101/2024.07.18.603996
Sci Rep. 2024 Jul 31. 14(1): 17639

GDNF/GFRA1 signaling contributes to chemo- and radioresistance in glioblastoma.

Inès C N Avenel, Jesper D Ewald, Jérémy Ariey-Bonnet, Ida H Kristensen, Stine A Petterson, Martin N Thesbjerg, Mark Burton, Mads Thomassen, Krister Wennerberg, Signe R Michaelsen, Bjarne W Kristensen.

Glioblastoma is the most common primary brain tumor in adults, characterized by an inherent aggressivity and resistance to treatment leading to poor prognoses. While some resistance mechanisms have been elucidated, a deeper understanding of these mechanisms is needed to increase therapeutic efficacy. In this study we first discovered glial-cell derived neurotrophic factor (GDNF) to be upregulated in patient-derived glioblastoma spheroid cultures after chemotherapeutic temozolomide treatment, through RNA-Seq experiments. Therefore, we investigated the role of the GDNF/GDNF receptor alpha 1 (GFRA1) signaling pathway as a resistance mechanism to chemotherapy with temozolomide and lomustine, as well as irradiation using patient-derived glioblastoma spheroid cultures. With qPCR experiments we showed a consistent upregulation of GDNF and its primary receptor GFRA1 following all three lines of treatment. Moreover, CRISPR/Cas9 knock-outs of GDNF in two patient-derived models sensitized these cells to chemotherapy treatment, but not radiotherapy. The increased sensitivity was completely reversed by the addition of exogeneous GDNF, confirming the key role of this factor in chemoresistance. Finally, a CRISPR KO of GFRA1 demonstrated a similar increased sensitivity to temozolomide and lomustine treatment, as well as radiotherapy. Together, our findings support the role of the GDNF/GFRA1 signaling pathway in glioblastoma chemo and radioresistance.

DOI: https://doi.org/10.1038/s41598-024-68626-x
Nat Med. 2024 Jul 31.

Cranioencephalic functional lymphoid units in glioblastoma.

Celia Dobersalske, Laurèl Rauschenbach, Yichao Hua, Christoph Berliner, Anita Steinbach, Anika Grüneboom, Konstantinos D Kokkaliaris, Dieter H Heiland, Pia Berger, Sarah Langer, Chin L Tan, Martin Stenzel, Somaya Landolsi, Flora Weber, Marvin Darkwah Oppong, Rudolf A Werner, Hanah Gull, Thomas Schröder, Thomas Linsenmann, Andreas K Buck, Matthias Gunzer, Martin Stuschke, Kathy Keyvani, Michael Forsting, Martin Glas, Jonathan Kipnis, Dennis A Steindler, Hans Christian Reinhardt, Edward W Green, Michael Platten, Alpaslan Tasdogan, Ken Herrmann, Florian Rambow, Igor Cima, Ulrich Sure, Björn Scheffler.

The ecosystem of brain tumors is considered immunosuppressed, but our current knowledge may be incomplete. Here we analyzed clinical cell and tissue specimens derived from patients presenting with glioblastoma or nonmalignant intracranial disease to report that the cranial bone (CB) marrow, in juxtaposition to treatment-naive glioblastoma tumors, harbors active lymphoid populations at the time of initial diagnosis. Clinical and anatomical imaging, single-cell molecular and immune cell profiling and quantification of tumor reactivity identified CD8+ T cell clonotypes in the CB that were also found in the tumor. These were characterized by acute and durable antitumor response rooted in the entire T cell developmental spectrum. In contrast to distal bone marrow, the CB niche proximal to the tumor showed increased frequencies of tumor-reactive CD8+ effector types expressing the lymphoid egress marker S1PR1. In line with this, cranial enhancement of CXCR4 radiolabel may serve as a surrogate marker indicating focal association with improved progression-free survival. The data of this study advocate preservation and further exploitation of these cranioencephalic units for the clinical care of glioblastoma.

DOI: https://doi.org/10.1038/s41591-024-03152-x
Nat Med. 2024 Aug 02.

Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells.

Chirayu R Chokshi, Muhammad Vaseem Shaikh, Benjamin Brakel, Martin A Rossotti, David Tieu, William Maich, Alisha Anand, Shawn C Chafe, Kui Zhai, Yujin Suk, Agata M Kieliszek, Petar Miletic, Nicholas Mikolajewicz, David Chen, Jamie D McNicol, Katherine Chan, Amy H Y Tong, Laura Kuhlmann, Lina Liu, Zahra Alizada, Daniel Mobilio, Nazanin Tatari, Neil Savage, Nikoo Aghaei, Shan Grewal, Anish Puri, Minomi Subapanditha, Dillon McKenna, Vladimir Ignatchenko, Joseph M Salamoun, Jacek M Kwiecien, Peter Wipf, Elizabeth R Sharlow, John P Provias, Jian-Qiang Lu, John S Lazo, Thomas Kislinger, Yu Lu, Kevin R Brown, Chitra Venugopal, Kevin A Henry, Jason Moffat, Sheila K Singh.

Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2 (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood-brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50-100% of mice. Our study identifies a promising multi-targetable PTP4A-ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.

DOI: https://doi.org/10.1038/s41591-024-03138-9
bioRxiv. 2024 Jul 24. pii: 2024.07.24.604840. [Epub ahead of print]

Glioblastoma Neurovascular Progenitor Orchestrates Tumor Cell Type Diversity.

Elisa Fazzari, Daria J Azizad, Kwanha Yu, Weihong Ge, Matthew X Li, Patricia R Nano, Ryan L Kan, Hong A Tum, Christopher Tse, Nicholas A Bayley, Vjola Haka, Dimitri Cadet, Travis Perryman, Jose A Soto, Brittney Wick, David R Raleigh, Elizabeth E Crouch, Kunal S Patel, Linda M Liau, Benjamin Deneen, David A Nathanson, Aparna Bhaduri.

Glioblastoma (GBM) is the deadliest form of primary brain tumor with limited treatment options. Recent studies have profiled GBM tumor heterogeneity, revealing numerous axes of variation that explain the molecular and spatial features of the tumor. Here, we seek to bridge descriptive characterization of GBM cell type heterogeneity with the functional role of individual populations within the tumor. Our lens leverages a gene program-centric meta-atlas of published transcriptomic studies to identify commonalities between diverse tumors and cell types in order to decipher the mechanisms that drive them. This approach led to the discovery of a tumor-derived stem cell population with mixed vascular and neural stem cell features, termed a neurovascular progenitor (NVP). Following in situ validation and molecular characterization of NVP cells in GBM patient samples, we characterized their function in vivo. Genetic depletion of NVP cells resulted in altered tumor cell composition, fewer cycling cells, and extended survival, underscoring their critical functional role. Clonal analysis of primary patient tumors in a human organoid tumor transplantation system demonstrated that the NVP has dual potency, generating both neuronal and vascular tumor cells. Although NVP cells comprise a small fraction of the tumor, these clonal analyses demonstrated that they strongly contribute to the total number of cycling cells in the tumor and generate a defined subset of the whole tumor. This study represents a paradigm by which cell type-specific interrogation of tumor populations can be used to study functional heterogeneity and therapeutically targetable vulnerabilities of GBM.

DOI: https://doi.org/10.1101/2024.07.24.604840
Elife. 2024 Aug 02. pii: RP96257. [Epub ahead of print]13

Dual targeting of histone deacetylases and MYC as potential treatment strategy for H3-K27M pediatric gliomas.

Danielle Algranati, Roni Oren, Bareket Dassa, Liat Fellus-Alyagor, Alexander Plotnikov, Haim Barr, Alon Harmelin, Nir London, Guy Ron, Noa Furth, Efrat Shema.

  Diffuse midline gliomas (DMGs) are aggressive and fatal pediatric tumors of the central nervous system that are highly resistant to treatments. Lysine to methionine substitution of residue 27 on histone H3 (H3-K27M) is a driver mutation in DMGs, reshaping the epigenetic landscape of these cells to promote tumorigenesis. H3-K27M gliomas are characterized by deregulation of histone acetylation and methylation pathways, as well as the oncogenic MYC pathway. In search of effective treatment, we examined the therapeutic potential of dual targeting of histone deacetylases (HDACs) and MYC in these tumors. Treatment of H3-K27M patient-derived cells with Sulfopin, an inhibitor shown to block MYC-driven tumors in vivo, in combination with the HDAC inhibitor Vorinostat, resulted in substantial decrease in cell viability. Moreover, transcriptome and epigenome profiling revealed synergistic effect of this drug combination in downregulation of prominent oncogenic pathways such as mTOR. Finally, in vivo studies of patient-derived orthotopic xenograft models showed significant tumor growth reduction in mice treated with the drug combination. These results highlight the combined treatment with PIN1 and HDAC inhibitors as a promising therapeutic approach for these aggressive tumors.

Keywords:  DMG; cancer biology; epigenetics; human; oncogene

DOI:  https://doi.org/10.7554/eLife.96257
Acta Neuropathol. 2024 Jul 29. 148(1): 12

Diffuse, IDH-wildtype gliomas in adults with minimal histological change and isolated TERT promoter mutation: not simply CNS WHO grade 4.

L P Priesterbach-Ackley, F Cordier, P de Witt Hamer, T J Snijders, P A Robe, B Küsters, W W J de Leng, W F A den Dunnen, D Brandsma, C Jansen, P Wesseling, A Muhlebner.

DOI: https://doi.org/10.1007/s00401-024-02773-3