bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022–08–14
eight papers selected by
Oltea Sampetrean, Keio University
  1. Neuronal Mechanisms Drive Whole Brain Invasion in Glioblastoma.
  2. Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma.
  3. Nonhematogenic circulating aneuploid cells confer inferior prognosis and therapeutic resistance in gliomas.
  4. Correction: Neurotensin promotes the progression of malignant glioma through NTSR1 and impacts the prognosis of glioma patients.
  5. Acidosis induces RIPK1-dependent death of glioblastoma stem cells via acid-sensing ion channel 1a.
  6. Incidence and characteristics of pseudoprogression in IDH-mutant high-grade gliomas: a POLA network study.
  7. PTEN inhibits AMPK to control collective migration.
  8. Engineered IL13 variants direct specificity of IL13Rα2-targeted CAR T cell therapy.
  1. Cancer Discov. 2022 Aug 12. OF1
    Neuronal Mechanisms Drive Whole Brain Invasion in Glioblastoma.
      Whole brain invasion of glioblastoma (GB) is driven by single GB cells with neuronal features.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-146
  2. Mol Cell. 2022 Aug 09. pii: S1097-2765(22)00647-5. [Epub ahead of print]
    Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma.
    Consuelo Torrini, Trang Thi Thu Nguyen, Chang Shu, Angeliki Mela, Nelson Humala, Aayushi Mahajan, Erin Heather Seeley, Guoan Zhang, Mike-Andrew Westhoff, Georg Karpel-Massler, Jeffrey N Bruce, Peter Canoll, Markus D Siegelin.
      Lactate accumulates to a significant amount in glioblastomas (GBMs), the most common primary malignant brain tumor with an unfavorable prognosis. However, it remains unclear whether lactate is metabolized by GBMs. Here, we demonstrated that lactate rescued patient-derived xenograft (PDX) GBM cells from nutrient-deprivation-mediated cell death. Transcriptome analysis, ATAC-seq, and ChIP-seq showed that lactate entertained a signature of oxidative energy metabolism. LC/MS analysis demonstrated that U-13C-lactate elicited substantial labeling of TCA-cycle metabolites, acetyl-CoA, and histone protein acetyl-residues in GBM cells. Lactate enhanced chromatin accessibility and histone acetylation in a manner dependent on oxidative energy metabolism and the ATP-citrate lyase (ACLY). Utilizing orthotopic PDX models of GBM, a combined tracer experiment unraveled that lactate carbons were substantially labeling the TCA-cycle metabolites. Finally, pharmacological blockage of oxidative energy metabolism extended overall survival in two orthotopic PDX models in mice. These results establish lactate metabolism as a novel druggable pathway for GBM.
    Keywords:  ATAC-seq; ChIP-seq; glioblastoma; lactate; metabolic flux analysis; tumor metabolism
    DOI:  https://doi.org/10.1016/j.molcel.2022.06.030
  3. Cancer Sci. 2022 Jul 30.
    Nonhematogenic circulating aneuploid cells confer inferior prognosis and therapeutic resistance in gliomas.
    Mingxiao Li, Faliang Gao, Xiaohui Ren, Gehong Dong, Hongyan Chen, Alexander Y Lin, Daisy Dandan Wang, Mingyang Liu, Peter Ping Lin, Shaoping Shen, Haihui Jiang, Chuanwei Yang, Xiaokang Zhang, Xuzhe Zhao, Qinghui Zhu, Ming Li, Yong Cui, Song Lin.
      Aneuploidy is the hallmark of malignancy. Our previous study successfully detected nonhematogenic circulating aneuploidy cells (CACs) in types of gliomas. The current prospective clinical study aims to further precisely subcategorize aneuploid CACs, including CD31- circulating tumor cells (CTCs) and CD31+ circulating tumor endothelial cells, and thoroughly investigate the clinical utilities of these different subtypes of cells. Co-detection and analysis of CTCs and circulating tumor-derived endothelial cells (CTECs) expressing CD133, glial fibrillary acidic protein (GFAP), or epidermal growth factor receptor variant III (EGFR vIII) were performed by integrated subtraction enrichment and immunostaining fluorescence in situ hybridization (SE-iFISH) in 111 preoperative primary diffuse glioma patients. Aneuploid CACs could be detected in most de novo glioma patients. Among detected CACs, 45.6% were CD31- /CD45- aneuploid CTCs and the remaining 54.4% were CD31+ /CD45- aneuploid CTECs. Positive detection of CTECs significantly correlated with disruption of the blood-brain barrier. The median number of large CTCs (L CTCs, >5 μm, 2) in low-grade glioma (WHO grade 2) was less than high-grade glioma (WHO grades 3 and 4) (3, p = 0.044), but this difference was not observed in small CTCs (S CTCs, ≤5 μm), CTECs or CACs (CTCs + CTECs). The numbers of CTCs, CTECs, or CACs in patients with contrast-enhancing (CE) lesions considerably exceeded that of non-CE lesions (p < 0.05). Receiver operating characteristic curves demonstrated that CD31+ CTECs, especially L CTECs, exhibited a close positive relationship with CE lesions. Survival analysis revealed that the high number of CD31- CTCs could be an adverse factor for compromised progression-free survival and overall survival. Longitudinal surveillance of CD31- CTCs was suitable for evaluating the therapeutic response and for monitoring potential emerging treatment resistance.
    Keywords:  CD31 + CTEC; blood-brain-barrier, CD31-CTC; glioma; prognosis; therapy resistance
    DOI:  https://doi.org/10.1111/cas.15516
  4. Mol Cancer. 2022 Aug 10. 21(1): 162
    Correction: Neurotensin promotes the progression of malignant glioma through NTSR1 and impacts the prognosis of glioma patients.
    Qing Ouyang, Xueyang Gong, Hualiang Xiao, Ji Zhou, Minhui Xu, Yun Dai, Lunshan Xu, Hua Feng, Hongjuan Cui, Liang Yi.
      
    DOI:  https://doi.org/10.1186/s12943-022-01632-7
  5. Cell Death Dis. 2022 Aug 12. 13(8): 702
    Acidosis induces RIPK1-dependent death of glioblastoma stem cells via acid-sensing ion channel 1a.
    Jan Clusmann, Klaus-Daniel Cortés Franco, David Alejandro Corredor Suárez, Istvan Katona, Maria Girbes Minguez, Nina Boersch, Karolos-Philippos Pissas, Jakob Vanek, Yuemin Tian, Stefan Gründer.
      Eliciting regulated cell death, like necroptosis, is a potential cancer treatment. However, pathways eliciting necroptosis are poorly understood. It has been reported that prolonged activation of acid-sensing ion channel 1a (ASIC1a) induces necroptosis in mouse neurons. Glioblastoma stem cells (GSCs) also express functional ASIC1a, but whether prolonged activation of ASIC1a induces necroptosis in GSCs is unknown. Here we used a tumorsphere formation assay to show that slight acidosis (pH 6.6) induces necrotic cell death in a manner that was sensitive to the necroptosis inhibitor Nec-1 and to the ASIC1a antagonist PcTx1. In addition, genetic knockout of ASIC1a rendered GSCs resistant to acid-induced reduction in tumorsphere formation, while the ASIC1 agonist MitTx1 reduced tumorsphere formation also at neutral pH. Finally, a 20 amino acid fragment of the ASIC1 C-terminus, thought to interact with the necroptosis kinase RIPK1, was sufficient to reduce the formation of tumorspheres. Meanwhile, the genetic knockout of MLKL, the executive protein in the necroptosis cascade, did not prevent a reduction in tumor sphere formation, suggesting that ASIC1a induced an alternative cell death pathway. These findings demonstrate that ASIC1a is a death receptor on GSCs that induces cell death during prolonged acidosis. We propose that this pathway shapes the evolution of a tumor in its acidic microenvironment and that pharmacological activation of ASIC1a might be a potential new strategy in tumor therapy.
    DOI:  https://doi.org/10.1038/s41419-022-05139-3
  6. Neuro Oncol. 2022 Aug 12. pii: noac194. [Epub ahead of print]
    Incidence and characteristics of pseudoprogression in IDH-mutant high-grade gliomas: a POLA network study.
    POLA Network
       BACKGROUND: Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described.
    METHODS: We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (with or without chemotherapy), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n=200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n=543) based on progression free survival before and after first progression.
    RESULTS: In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5 months after radiotherapy. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted in the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2 years after radiotherapy. The only factor associated with pseudoprogression occurrence was adjuvant PCV chemotherapy. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions.
    CONCLUSION: In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2 years after radiotherapy, the possibility of a pseudoprogression should be carefully considered.
    Keywords:  High-grade glioma; IDH-mutant; chemotherapy; pseudoprogression; radiotherapy
    DOI:  https://doi.org/10.1093/neuonc/noac194
  7. Nat Commun. 2022 Aug 11. 13(1): 4528
    PTEN inhibits AMPK to control collective migration.
    Florent Peglion, Lavinia Capuana, Isabelle Perfettini, Laurent Boucontet, Ben Braithwaite, Emma Colucci-Guyon, Emie Quissac, Karin Forsberg-Nilsson, Flora Llense, Sandrine Etienne-Manneville.
      Pten is one of the most frequently mutated tumour suppressor gene in cancer. PTEN is generally altered in invasive cancers such as glioblastomas, but its function in collective cell migration and invasion is not fully characterised. Herein, we report that the loss of PTEN increases cell speed during collective migration of non-tumourous cells both in vitro and in vivo. We further show that loss of PTEN promotes LKB1-dependent phosphorylation and activation of the major metabolic regulator AMPK. In turn AMPK increases VASP phosphorylation, reduces VASP localisation at cell-cell junctions and decreases the interjunctional transverse actin arcs at the leading front, provoking a weakening of cell-cell contacts and increasing migration speed. Targeting AMPK activity not only slows down PTEN-depleted cells, it also limits PTEN-null glioblastoma cell invasion, opening new opportunities to treat glioblastoma lethal invasiveness.
    DOI:  https://doi.org/10.1038/s41467-022-31842-y
  8. Proc Natl Acad Sci U S A. 2022 Aug 16. 119(33): e2112006119
    Engineered IL13 variants direct specificity of IL13Rα2-targeted CAR T cell therapy.
    Lawrence A Stern, Sharareh Gholamin, Ignacio Moraga, Xin Yang, Supraja Saravanakumar, Joseph R Cohen, Renate Starr, Brenda Aguilar, Vanessa Salvary, Jonathan C Hibbard, Anusha Kalbasi, Jennifer K Shepphird, James O'Hearn, K Christopher Garcia, Christine E Brown.
      IL13Rα2 is an attractive target due to its overexpression in a variety of cancers and rare expression in healthy tissue, motivating expansion of interleukin 13 (IL13)-based chimeric antigen receptor (CAR) T cell therapy from glioblastoma into systemic malignancies. IL13Rα1, the other binding partner of IL13, is ubiquitously expressed in healthy tissue, raising concerns about the therapeutic window of systemic administration. IL13 mutants with diminished binding affinity to IL13Rα1 were previously generated by structure-guided protein engineering. In this study, two such variants, termed C4 and D7, are characterized for their ability to mediate IL13Rα2-specific response as binding domains for CAR T cells. Despite IL13Rα1 and IL13Rα2 sharing similar binding interfaces on IL13, mutations to IL13 that decrease binding affinity for IL13Rα1 did not drastically change binding affinity for IL13Rα2. Micromolar affinity to IL13Rα1 was sufficient to pacify IL13-mutein CAR T cells in the presence of IL13Rα1-overexpressing cells in vitro. Interestingly, effector activity of D7 CAR T cells, but not C4 CAR T cells, was demonstrated when cocultured with IL13Rα1/IL4Rα-coexpressing cancer cells. While low-affinity interactions with IL13Rα1 did not result in observable toxicities in mice, in vivo biodistribution studies demonstrated that C4 and D7 CAR T cells were better able to traffic away from IL13Rα1+ lung tissue than were wild-type (WT) CAR T cells. These results demonstrate the utility of structure-guided engineering of ligand-based binding domains with appropriate selectivity while validating IL13-mutein CARs with improved selectivity for application to systemic IL13Rα2-expressing malignancies.
    Keywords:  CARs; IL13Rα2; T cells; chimeric antigen receptors; glioblastoma
    DOI:  https://doi.org/10.1073/pnas.2112006119
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