bims-malgli 2024-08-11 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2024–08–11
thirteen papers selected by
Oltea Sampetrean, Keio University

Targeted radionuclide therapy for gliomas: emerging clinical trial landscape.
IRF8-driven reprogramming of the immune microenvironment enhances anti-tumor adaptive immunity and reduces immunosuppression in murine glioblastoma.
CircVPS8 promotes the malignant phenotype and inhibits ferroptosis of glioma stem cells by acting as a scaffold for MKRN1, SOX15 and HNF4A.
Multi-omics and pharmacological characterization of patient-derived glioma cell lines.
Exploring molecular glioblastoma: Insights from advanced imaging for a nuanced understanding of the molecularly defined malignant biology.
Cell-specific cross-talk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone.
Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma.
Glioblastoma vulnerability to neddylation inhibition is dependent on PTEN status, and dysregulation of the cell cycle and DNA replication.
TSPAN4 influences glioblastoma progression through regulating EGFR stability.
CCL2 mediated IKZF1 expression promotes M2 polarization of glioma-associated macrophages through CD84-SHP2 pathway.
Lactylation: Linking the Warburg effect to DNA damage repair.
Sacituzumab Govitecan in patients with breast cancer brain metastases and recurrent glioblastoma: a phase 0 window-of-opportunity trial.
The DNA methylome of pediatric brain tumors appears shaped by structural variation and predicts survival.

Neuro Oncol. 2024 Aug 06. pii: noae125. [Epub ahead of print]

Targeted radionuclide therapy for gliomas: emerging clinical trial landscape.

Michael Weller, Nathalie L Albert, Norbert Galldiks, Andrea Bink, Matthias Preusser, Erik P Sulman, Valerie Treyer, Patrick Y Wen, Joerg C Tonn, Emilie Le Rhun.

  According to the new WHO classification of 2021, gliomas are a heterogeneous group of tumors with very different histology, molecular genetics and prognoses. In addition to glioblastomas, the most common gliomas, there are also numerous less common gliomas, some of which have a very favorable prognosis. Targeted radionuclide therapy is a therapeutic option that can be attractive if a tumor can be targeted based on its molecular characteristics. It is particularly useful when tumors cannot be completely resected or when conventional imaging does not fully capture the extent of the tumor. Numerous approaches to radionuclide therapy for gliomas are in early development. The most advanced approaches for patients with gliomas in the clinic employ L-type amino acid transporter 1 as an uptake mechanism for radiolabeled amino acids or target somatostatin receptor 2 or gastrin-releasing peptide receptor. Here, we discuss the various target structures of radionuclide therapy in gliomas and provide an outlook for which glioma entities radionuclide therapy could most likely provide a therapeutic alternative.

Keywords:  atrocytoma; glioblastoma; oligodendroglioma; personnalized medicine; theranostic

DOI:  https://doi.org/10.1093/neuonc/noae125
Neuro Oncol. 2024 Aug 08. pii: noae149. [Epub ahead of print]

IRF8-driven reprogramming of the immune microenvironment enhances anti-tumor adaptive immunity and reduces immunosuppression in murine glioblastoma.

Megan Montoya, Sara A Collins, Pavlina Chuntova, Trishna S Patel, Takahide Nejo, Akane Yamamichi, Noriyuki Kasahara, Hideho Okada.

   BACKGROUND: Glioblastoma (GBM) has a highly immunosuppressive tumor immune microenvironment (TIME), largely mediated by myeloid-derived suppressor cells (MDSCs). Here, we utilized a retroviral replicating vector (RRV) to deliver Interferon Regulatory Factor 8 (IRF8), a master regulator of type 1 conventional dendritic cell (cDC1) development, in a syngeneic murine GBM model. We hypothesized that RRV-mediated delivery of IRF8 could "reprogram" intratumoral MDSCs into antigen-presenting cells (APCs) and thereby restore T-cell responses.
METHODS: Effects of RRV-IRF8 on survival and tumor growth kinetics were examined in the SB28 murine GBM model. Immunophenotype was analyzed by flow cytometry and gene expression assays. We assayed functional immunosuppression and antigen presentation by ex vivo T-cell-myeloid co-culture.
RESULTS: Intratumoral injection of RRV-IRF8 in mice bearing intracerebral SB28 glioma significantly suppressed the tumor growth and prolonged survival. RRV-IRF8 treated tumors exhibited significant enrichment of cDC1s and CD8+ T-cells. Additionally, myeloid cells derived from RRV-IRF8 tumors showed decreased expression of the immunosuppressive markers Arg1 and IDO1 and demonstrated reduced suppression of naïve T-cell proliferation in ex vivo co-culture, compared to controls. Furthermore, DCs from RRV-IRF8 tumors showed increased antigen presentation compared to those from control tumors. In vivo treatment with azidothymidine (AZT), a viral replication inhibitor, showed that IRF8 transduction in both tumor and non-tumor cells is necessary for survival benefit, associated with a reprogrammed, cDC1- and CD8 T-cell-enriched TIME.
CONCLUSIONS: Our results indicate that reprogramming of glioma-infiltrating myeloid cells by in vivo expression of IRF8 may reduce immunosuppression and enhance antigen presentation, achieving improved tumor control.

Keywords:  Glioblastoma; IRF8; Immunosuppression; MDSC; RRV-mediated gene therapy

DOI:  https://doi.org/10.1093/neuonc/noae149
Oncogene. 2024 Aug 04.

CircVPS8 promotes the malignant phenotype and inhibits ferroptosis of glioma stem cells by acting as a scaffold for MKRN1, SOX15 and HNF4A.

Jinpeng Hu, Xinqiao Li, Kai Xu, Junhua Chen, Shengliang Zong, Haiying Zhang, Hao Li, Guoqing Zhang, Zhengting Guo, Xiang Zhao, Yang Jiang, Zhitao Jing.

Exciting breakthroughs have been achieved in the field of glioblastoma with therapeutic interventions targeting specific ferroptosis targets. Nonetheless, the precise mechanisms through which circRNAs regulate the ferroptosis pathway have yet to be fully elucidated. Here we have identified a novel circRNA, circVPS8, which is highly expressed in glioblastoma. Our findings demonstrated that circVPS8 enhances glioma stem cells' viability, proliferation, sphere-forming ability, and stemness. Additionally, it inhibits ferroptosis in GSCs. In vivo, experiments further supported the promotion of glioblastoma growth by circVPS8. Mechanistically, circVPS8 acts as a scaffold, binding to both MKRN1 and SOX15, thus facilitating the ubiquitination of MKRN1 and subsequent degradation of SOX15. Due to competitive binding, the ubiquitination ability of MKRN1 towards HNF4A is reduced, leading to elevated HNF4A expression. Increased HNF4A expression, along with decreased SOX15 expression, synergistically inhibits ferroptosis in glioblastoma. Overall, our study highlights circVPS8 as a promising therapeutic target and provides valuable insights for clinically targeted therapy of glioblastoma.

DOI: https://doi.org/10.1038/s41388-024-03116-y
Nat Commun. 2024 Aug 08. 15(1): 6740

Multi-omics and pharmacological characterization of patient-derived glioma cell lines.

Min Wu, Tingting Wang, Nan Ji, Ting Lu, Ran Yuan, Lingxiang Wu, Junxia Zhang, Mengyuan Li, Penghui Cao, Jiarui Zhao, Guanzhang Li, Jianyu Li, Yu Li, Yujie Tang, Zhengliang Gao, Xiuxing Wang, Wen Cheng, Ming Ge, Gang Cui, Rui Li, Anhua Wu, Yongping You, Wei Zhang, Qianghu Wang, Jian Chen.

Glioblastoma (GBM) is the most common brain tumor and remains incurable. Primary GBM cultures are widely used tools for drug screening, but there is a lack of genomic and pharmacological characterization for these primary GBM cultures. Here, we collect 50 patient-derived glioma cell (PDGC) lines and characterize them by whole genome sequencing, RNA sequencing, and drug response screening. We identify three molecular subtypes among PDGCs: mesenchymal (MES), proneural (PN), and oxidative phosphorylation (OXPHOS). Drug response profiling reveals that PN subtype PDGCs are sensitive to tyrosine kinase inhibitors, whereas OXPHOS subtype PDGCs are sensitive to histone deacetylase inhibitors, oxidative phosphorylation inhibitors, and HMG-CoA reductase inhibitors. PN and OXPHOS subtype PDGCs stably form tumors in vivo upon intracranial transplantation into immunodeficient mice, whereas most MES subtype PDGCs fail to form tumors in vivo. In addition, PDGCs cultured by serum-free medium, especially long-passage PDGCs, carry MYC/MYCN amplification, which is rare in GBM patients. Our study provides a valuable resource for understanding primary glioma cell cultures and clinical translation and highlights the problems of serum-free PDGC culture systems that cannot be ignored.

DOI: https://doi.org/10.1038/s41467-024-51214-y
Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae106

Exploring molecular glioblastoma: Insights from advanced imaging for a nuanced understanding of the molecularly defined malignant biology.

Michael Griessmair, Claire Delbridge, Julian Ziegenfeuter, Kirsten Jung, Tobias Mueller, Severin Schramm, Denise Bernhardt, Friederike Schmidt-Graf, Olivia Kertels, Marie Thomas, Claus Zimmer, Bernhard Meyer, Stephanie E Combs, Igor Yakushev, Benedikt Wiestler, Marie-Christin Metz.

   Background: Molecular glioblastoma (molGB) does not exhibit the histologic hallmarks of a grade 4 glioma but is nevertheless diagnosed as glioblastoma when harboring specific molecular markers. MolGB can easily be mistaken for similar-appearing lower-grade astrocytomas. Here, we investigated how advanced imaging could reflect the underlying tumor biology.
Methods: Clinical and imaging data were collected for 7 molGB grade 4, 9 astrocytomas grade 2, and 12 astrocytomas grade 3. Four neuroradiologists performed VASARI-scoring of conventional imaging, and their inter-reader agreement was assessed using Fleiss κ coefficient. To evaluate the potential of advanced imaging, 2-sample t test, 1-way ANOVA, Mann-Whitney U, and Kruskal-Wallis test were performed to test for significant differences between apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) that were extracted fully automatically from the whole tumor volume.
Results: While conventional VASARI imaging features did not allow for reliable differentiation between glioma entities, rCBV was significantly higher in molGB compared to astrocytomas for the 5th and 95th percentile, mean, and median values (P < .05). ADC values were significantly lower in molGB than in astrocytomas for mean, median, and the 95th percentile (P < .05). Although no molGB showed contrast enhancement initially, we observed enhancement in the short-term follow-up of 1 patient.
Discussion: Quantitative analysis of diffusion and perfusion parameters shows potential in reflecting the malignant tumor biology of molGB. It may increase awareness of molGB in a nonenhancing, "benign" appearing tumor. Our results support the emerging hypothesis that molGB might present glioblastoma captured at an early stage of gliomagenesis.

Keywords:  850k methylation analysis; advanced imaging biomarkers; fully automated tumor segmentations; tumorigenesis of glioblastoma

DOI:  https://doi.org/10.1093/noajnl/vdae106
Sci Adv. 2024 Aug 09. 10(32): eadn1607

Cell-specific cross-talk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone.

Emily S Norton, Lauren A Whaley, Vanessa K Jones, Mieu M Brooks, Marissa N Russo, Dmytro Morderer, Erik Jessen, Paula Schiapparelli, Andres Ramos-Fresnedo, Natanael Zarco, Anna Carrano, Wilfried Rossoll, Yan W Asmann, TuKiet T Lam, Kaisorn L Chaichana, Panos Z Anastasiadis, Alfredo Quiñones-Hinojosa, Hugo Guerrero-Cázares.

Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially because of subventricular zone contact. Despite this, cross-talk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. In addition, GBM brain tumor-initiating cells (BTICs) increase expression of cathepsin B (CTSB) upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal that both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Last, we show LV-proximal CTSB up-regulation in patients, showing the relevance of this cross-talk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.

DOI: https://doi.org/10.1126/sciadv.adn1607
Cell Metab. 2024 Aug 06. pii: S1550-4131(24)00282-1. [Epub ahead of print]36(8): 1696-1710.e10

Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma.

Guanzhang Li, Di Wang, You Zhai, Changqing Pan, Jiazheng Zhang, Chen Wang, Ruoyu Huang, Mingchen Yu, Yiming Li, Xing Liu, Yanwei Liu, Fan Wu, Zheng Zhao, Huimin Hu, Zhongfang Shi, Ulf Dietrich Kahlert, Tao Jiang, Wei Zhang.

  Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3 and PKM2 enhances the latter's tetramerization and promotes lactate accumulation in glioblastoma stem cells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin α, allowing for greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening of a small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show that ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3hi GBM.

Keywords:  ALDH1A3; PKM2; glioblastoma; lactylation; therapeutic resistance

DOI:  https://doi.org/10.1016/j.cmet.2024.07.011
Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae104

Glioblastoma vulnerability to neddylation inhibition is dependent on PTEN status, and dysregulation of the cell cycle and DNA replication.

Brett Taylor, Nanyun Tang, Yue Hao, Matthew Lee, Sen Peng, Rita Bybee, Lauren Hartman, Krystine Garcia-Mansfield, Ritin Sharma, Patrick Pirrotte, Jianhui Ma, Alison D Parisian, Frank Furnari, Harshil D Dhruv, Michael E Berens.

   Background: Neddylation (NAE) inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report the cytotoxic vulnerability to NAE inhibitors in a subset of glioblastoma (GBM) preclinical models and identify genetic alterations and biological processes underlying differential response.
Methods: GBM DNA sequencing and transcriptomic data were queried for genes associated with response to NAE inhibition; candidates were validated by molecular techniques. Multi-omics and functional assays revealed processes implicated in NAE inhibition response.
Results: Transcriptomics and shotgun proteomics depict PTEN signaling, DNA replication, and DNA repair pathways as significant differentiators between sensitive and resistant models. Vulnerability to MLN4924, a NAE inhibitor, is associated with elevated S-phase populations, DNA re-replication, and DNA damage. In a panel of GBM models, loss of WT PTEN is associated with resistance to different NAE inhibitors. A NAE inhibition response gene set could segregate the GBM cell lines that are most resistant to MLN4924.
Conclusions: Loss of WT PTEN is associated with non-sensitivity to 3 different compounds that inhibit NAE in GBM. A NAE inhibition response gene set largely consisting of DNA replication genes could segregate GBM cell lines most resistant to NAEi and may be the basis for future development of NAE inhibition signatures of vulnerability and clinical trial enrollment within a precision medicine paradigm.

Keywords:  DNA replication; Neddylation; PTEN; glioblastoma; multi-omics

DOI:  https://doi.org/10.1093/noajnl/vdae104
iScience. 2024 Aug 16. 27(8): 110417

TSPAN4 influences glioblastoma progression through regulating EGFR stability.

Yanbin Dong, Xiaolong Tang, Wenhui Zhao, Ping Liu, Weiru Yu, Jinlai Ren, Yu Chen, Yanfang Cui, Juan Chen, Yongshuo Liu.

  Glioblastoma (GBM) is characterized by high morbidity, mortality, and low cure rates. Recent studies suggest that TSPAN4 is recognized as a marker protein for migrasomes, a vesicular organelle associated with cell migration. However, the intrinsic role of TSPAN4 in cancers has not been clarified, especially in GBM. Here, we report that TSPAN4 promotes GBM progression by interacting with epidermal growth factor receptor (EGFR) and regulating its stability. Clinically, TSPAN4 is highly expressed in GBM and is significantly correlated with poor prognosis. Functionally, TSPAN4 knockdown dramatically inhibits GBM cell proliferation and invasion in vitro, as well as tumorigenicity in vivo. Conversely, overexpression of TSPAN4 facilitates GBM progression. Mechanistically, TSPAN4 knockdown disrupts interaction with EGFR, destabilizing its expression and inactivating EGFR and downstream signaling pathways, such as MEK/ERK, STAT3, and AKT. Our study reveals that TSPAN4 drives GBM progression through regulating EGFR stability and could be a potential target for cancer therapy.

Keywords:  Biological sciences; Molecular biology; Molecular medicine; Natural sciences

DOI:  https://doi.org/10.1016/j.isci.2024.110417
Oncogene. 2024 Aug 07.

CCL2 mediated IKZF1 expression promotes M2 polarization of glioma-associated macrophages through CD84-SHP2 pathway.

Yifu Song, Yaochuan Zhang, Zixun Wang, Yibin Lin, Xu Cao, Xiaodi Han, Guangyu Li, Ana Hou, Sheng Han.

The proneural-mesenchymal (PN-MES) transformation of glioma stem cells (GSCs) can significantly increase proliferation, invasion, chemotherapy tolerance, and recurrence. M2-like polarization of tumor-associated macrophages (TAMs) has a strong immunosuppressive effect, promoting tumor malignancy and angiogenesis. There is limited understanding on the interactions between GSCs and TAMs as well as their associated molecular mechanisms. In the present study, bioinformatics analysis, GSC and TAM co-culture, determination of TAM polarization phenotypes, and other in vitro experiments confirmed that CCL2 secreted by MES-GSCs promotes TAM-M2 polarization via the IKZF1-CD84-SHP2 pathway and PN-MES transformation of GSCs via the IKZF1-LRG1 pathway in TAMs. IKZF1 inhibitors could significantly reduce tumor volumes in animal glioma models and improve survival, as well as suppress TAM-M2 polarization and the GSC malignant phenotype. The results of this study indicate the important interaction between TAMs and GSCs in the glioma microenvironment as well as its role in tumor progression. The findings also suggest a novel target for follow-up clinical transformation research on the regulation of TAM function and GSCs malignant phenotype.

DOI: https://doi.org/10.1038/s41388-024-03118-w
Cell Metab. 2024 Aug 06. pii: S1550-4131(24)00271-7. [Epub ahead of print]36(8): 1637-1639

Lactylation: Linking the Warburg effect to DNA damage repair.

Peng Sun, Leina Ma, Zhimin Lu.

In this issue of Cell Metabolism, Li et al. report that the highly expressed aldehyde dehydrogenase 1 family member A3 interacts with pyruvate kinase M2 (PKM2) in glioblastoma cells. Consequently, PKM2 tetramerization and activation promote lactate production, leading to the lactylation and nuclear translocation of XRCC1 for DNA damage repair and therapeutic resistance.

DOI: https://doi.org/10.1016/j.cmet.2024.06.015
Nat Commun. 2024 Aug 07. 15(1): 6707

Sacituzumab Govitecan in patients with breast cancer brain metastases and recurrent glioblastoma: a phase 0 window-of-opportunity trial.

Henriette U Balinda, William J Kelly, Virginia G Kaklamani, Kate I Lathrop, Marcela Mazo Canola, Pegah Ghamasaee, Gangadhara R Sareddy, Joel Michalek, Andrea R Gilbert, Prathibha Surapaneni, Stefano Tiziani, Renu Pandey, Jennifer Chiou, Alessia Lodi, John R Floyd, Andrew J Brenner.

Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .

DOI: https://doi.org/10.1038/s41467-024-50558-9
Nat Commun. 2024 Aug 08. 15(1): 6775

The DNA methylome of pediatric brain tumors appears shaped by structural variation and predicts survival.

Fengju Chen, Yiqun Zhang, Lanlan Shen, Chad J Creighton.

Structural variation heavily influences the molecular landscape of cancer, in part by impacting DNA methylation-mediated transcriptional regulation. Here, using multi-omic datasets involving >2400 pediatric brain and central nervous system tumors of diverse histologies from the Children's Brain Tumor Network, we report hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of somatic structural variant (SV) breakpoints is recurrently associated with altered expression or DNA methylation, respectively, including tumor suppressor genes ATRX and CDKN2A. Altered DNA methylation near enhancers associates with nearby somatic SV breakpoints, including MYC and MYCN. A subset of genes with SV-CGI methylation associations also have expression associations with patient survival, including BCOR, TERT, RCOR2, and PDLIM4. DNA methylation changes in recurrent or progressive tumors compared to the initial tumor within the same patient can predict survival in pediatric and adult cancers. Our comprehensive and pan-histology genomic analyses reveal mechanisms of noncoding alterations impacting cancer genes.

DOI: https://doi.org/10.1038/s41467-024-51276-y