bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–06–23
nine papers selected by
Oltea Sampetrean, Keio University
  1. Glioma-derived M-CSF and IL-34 license M-MDSCs to suppress CD8 + T cells in a NOS-dependent manner.
  2. PTP4A2 Promotes Glioblastoma Progression and Macrophage Polarization Under Microenvironmental Pressure.
  3. Metabolic Profiling of Glioblastoma Stem Cells Reveals Pyruvate Carboxylase as a Critical Survival Factor and Potential Therapeutic Target.
  4. Sex differences in glioblastoma based on tumor subtypes.
  5. ATM inhibition exploits checkpoint defects and ATM-dependent double strand break repair in TP53-mutant glioblastoma.
  6. Single nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of combined CDK4/6 and mTOR inhibition in a phase 0/1 trial of recurrent high-grade glioma.
  7. The Sybil prophecy: Searching for predictors of response to bevacizumab in glioblastoma.
  8. Resistance to Spindle Inhibitors in Glioblastoma Depends on STAT3 and Therapy Induced Senescence.
  9. Targeting the sphingolipid rheostat in IDH1 mut glioma alters cholesterol homeostasis and triggers apoptosis via membrane degradation.
  1. bioRxiv. 2024 Jun 06. pii: 2024.06.05.597474. [Epub ahead of print]
    Glioma-derived M-CSF and IL-34 license M-MDSCs to suppress CD8 + T cells in a NOS-dependent manner.
    Gregory P Takacs, Julia S Garcia, Caitlyn A Hodges, Christian J Kreiger, Alexandra Sherman, Jeffrey K Harrison.
      Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2 + /CX3CR1 + M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2 + /CX3CR1 + cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that are driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.
    Simple Summary: Currently there are no effective therapies for glioblastoma. Infiltrating myeloid cells contribute significantly to the immune suppressive tumor microenvironment that is characteristic of GBM. Monocytic myeloid derived suppressor cells are chief immune suppressive cells found in the glioma microenvironment. Understanding the mechanisms of M-MDSC differentiation and T cell suppression is imperative for generating therapies that target this tumor supportive cell population. In this study we found that glioma secreted CSF1R ligands, M-CSF and IL-34, license M-MDSCs to suppress CD8 T cells. These M-MDSCs partially utilize nitric oxide synthase to illicit their suppressive activity. However, spatial RNAseq points to glioma microenvironment niches driving M-MDSC heterogeneity. Our findings identify key regulators of differentiation and suppressive mechanisms of M-MDSCs and confirm the importance of targeting this cell population in glioma.
    DOI:  https://doi.org/10.1101/2024.06.05.597474
  2. Cancer Res Commun. 2024 Jun 21.
    PTP4A2 Promotes Glioblastoma Progression and Macrophage Polarization Under Microenvironmental Pressure.
    Tiffanie Chouleur, Andrea Emanuelli, Wilfried Souleyreau, Marie-Alix Derieppe, Teo Leboucq, Serge Hardy, Thomas Mathivet, Michel L Tremblay, Andreas Bikfalvi.
      Phosphatase of Regenerating Liver-2 (PRL2; also known as PTP4A2) has been linked to cancer progression. Still, its exact role in glioblastoma (GB), the most aggressive type of primary brain tumor, remains elusive. Here we report that pharmacological treatment using JMS-053, a pan-PRL inhibitor, inhibits GB cell viability and spheroids growth. We also show that PTP4A2 is associated with a poor prognosis in gliomas, and its expression correlates with GBM aggressiveness. Using a GB orthotopic xenograft model, we show that PTP4A2 overexpression promotes tumor growth and reduces mouse survival. Furthermore, PTP4A2 deletion leads to increased apoptosis and pro-inflammatory signals. Using a syngeneic GB model, depletion of PTP4A2 reduces tumor growth and induces a shift in the tumor microenvironment towards an immunosuppressive state. In vitro assays show that cell proliferation is not affected in PTP4A2 deficient or overexpressing cells highlighting the importance of the microenvironment in PTP4A2 functions. Collectively, our results indicate that PTP4A2 promotes GB growth in response to microenvironmental pressure and supports the targeting of PTP4A2 as therapeutic strategy against GB.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-23-0334
  3. Neuro Oncol. 2024 Jun 13. pii: noae106. [Epub ahead of print]
    Metabolic Profiling of Glioblastoma Stem Cells Reveals Pyruvate Carboxylase as a Critical Survival Factor and Potential Therapeutic Target.
    Ophélie Renoult, Mélanie Laurent-Blond, Hala Awada, Lisa Oliver, Noémie Joalland, Mikaël Croyal, François Paris, Catherine Gratas, Claire Pecqueur.
       BACKGROUND: Glioblastoma (GBM) is a highly aggressive tumor with unmet therapeutic needs, which can be explained by extensive intra-tumoral heterogeneity and plasticity. In this study, we aimed to investigate the specific metabolic features of Glioblastoma stem cells (GSC), a rare tumor subpopulation involved in tumor growth and therapy resistance.
    METHODS: We conducted comprehensive analyses of primary patient-derived GBM cultures and GSC-enriched cultures of human GBM cell lines using state-of-the-art molecular, metabolic and phenotypic studies.
    RESULTS: We showed that GSC-enriched cultures display distinct glycolytic profiles compared with differentiated tumor cells. Further analysis revealed that GSC relies on pyruvate carboxylase activity for survival and self-renewal capacity. Interestingly, inhibition of pyruvate carboxylase led to GSC death, particularly when the glutamine pool was low, and increased differentiation. Finally, while GSC displayed resistance to the chemotherapy drug etoposide, genetic or pharmacological inhibition of pyruvate carboxylase restored etoposide sensitivity in GSC, both in vitro and in orthotopic murine models.
    CONCLUSION: Our findings demonstrate the critical role of pyruvate carboxylase in GSC metabolism, survival and escape to etoposide. They also highlight pyruvate carboxylase as a therapeutic target to overcome therapy resistance in GBM.
    Keywords:  Cancer stem cells; glioblastoma; metabolic vulnerability; mitochondrial metabolism; pyruvate carboxylation
    DOI:  https://doi.org/10.1093/neuonc/noae106
  4. Neuro Oncol. 2024 Jun 17. pii: noae089. [Epub ahead of print]
    Sex differences in glioblastoma based on tumor subtypes.
    Berta Segura-Collar, Ricardo Gargini.
      
    DOI:  https://doi.org/10.1093/neuonc/noae089
  5. Nat Commun. 2024 Jun 21. 15(1): 5294
    ATM inhibition exploits checkpoint defects and ATM-dependent double strand break repair in TP53-mutant glioblastoma.
    Daniel J Laverty, Shiv K Gupta, Gary A Bradshaw, Alexander S Hunter, Brett L Carlson, Nery Matias Calmo, Jiajia Chen, Shulan Tian, Jann N Sarkaria, Zachary D Nagel.
      Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR and MMEJ activity, suggesting that these pathways contribute to treatment resistance. We screen clinically relevant small molecules for DSBR inhibition with the aim of identifying improved GBM combination therapy regimens. We identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor that suppresses radiation-induced phosphorylation of DSBR proteins, blocks DSB end resection, and enhances the cytotoxic effects of TMZ in treatment-naïve and treatment-resistant GBMs with TP53 mutation. We further show that a combination of G2/M checkpoint deficiency and reliance upon ATM-dependent DSBR renders TP53 mutant GBMs hypersensitive to TMZ/AZD1390 and radiation/AZD1390 combinations. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.
    DOI:  https://doi.org/10.1038/s41467-024-49316-8
  6. medRxiv. 2024 Jun 07. pii: 2024.06.07.24308439. [Epub ahead of print]
    Single nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of combined CDK4/6 and mTOR inhibition in a phase 0/1 trial of recurrent high-grade glioma.
    Kevin C Johnson, An-Chi Tien, Jun Jiang, James McNamara, Yu-Wei Chang, Chelsea Montgomery, Anita DeSantis, Leonel Elena-Sanchez, Yoko Fujita, Seongho Kim, Avishay Spitzer, Paul Gabriel, William F Flynn, Elise T Courtois, Amy Hong, Jocelyn Harmon, Yoshie Umemura, Artak Tovmasyan, Jing Li, Shwetal Mehta, Roel Verhaak, Nader Sanai.
      Outcomes for adult patients with a high-grade glioma continue to be dismal and new treatment paradigms are urgently needed. To optimize the opportunity for discovery, we performed a phase 0/1 dose-escalation clinical trial that investigated tumor pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics following combined ribociclib (CDK4/6 inhibitor) and everolimus (mTOR inhibitor) treatment in recurrent high-grade glioma. Patients with a recurrent high-grade glioma (n = 24) harboring 1) CDKN2A / B deletion or CDK4 / 6 amplification, 2) PTEN loss or PIK3CA mutations, and 3) wild-type retinoblastoma protein (Rb) were enrolled. Patients received neoadjuvant ribociclib and everolimus treatment and no dose-limiting toxicities were observed. The median unbound ribociclib concentrations in Gadolinium non-enhancing tumor regions were 170 nM (range, 65 - 1770 nM) and 634 nM (range, 68 - 2345 nM) in patients receiving 5 days treatment at the daily dose of 400 and 600 mg, respectively. Unbound everolimus concentrations were below the limit of detection (< 0.1 nM) in both enhancing and non-enhancing tumor regions at all dose levels. We identified a significant decrease in MIB1 positive cells suggesting ribociclib-associated cell cycle inhibition. Single nuclei RNAseq (snRNA) based comparisons of 17 IDH-wild-type on-trial recurrences to 31 IDH-wild-type standard of care treated recurrences data demonstrated a significantly lower fraction of cycling and neural progenitor-like (NPC-like) malignant cell populations. We validated the CDK4/6 inhibitor-directed malignant cell state shifts using three patient-derived cell lines. The presented clinical trial highlights the value of integrating pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics to assess treatment effects in phase 0/1 surgical tissues, including malignant cell state shifts. ClinicalTrials.gov identifier: NCT03834740 .
    DOI:  https://doi.org/10.1101/2024.06.07.24308439
  7. Neuro Oncol. 2024 Jun 17. pii: noae088. [Epub ahead of print]
    The Sybil prophecy: Searching for predictors of response to bevacizumab in glioblastoma.
    Martina Offi, Lucia Gabriele, Giulia Romagnoli, Liverana Lauretti, Roberto Pallini, Quintino Giorgio D'Alessandris.
      
    DOI:  https://doi.org/10.1093/neuonc/noae088
  8. bioRxiv. 2024 Jun 09. pii: 2024.06.09.598115. [Epub ahead of print]
    Resistance to Spindle Inhibitors in Glioblastoma Depends on STAT3 and Therapy Induced Senescence.
    Natanael Zarco, Athanassios Dovas, Virginea de Araujo Farias, Naveen Kh Nagaiah, Ashley Haddock, Peter A Sims, Dolores Hambardzumyan, Christian T Meyer, Peter Canoll, Steven S Rosenfeld, Rajappa S Kenchappa.
      While mitotic spindle inhibitors specifically kill proliferating tumor cells without the toxicities of microtubule poisons, resistance has limited their clinical utility. Treating glioblastomas with the spindle inhibitors ispinesib, alisertib, or volasertib creates a subpopulation of therapy induced senescent cells that resist these drugs by relying upon the anti-apoptotic and metabolic effects of activated STAT3. Furthermore, these senescent cells expand the repertoire of cells resistant to these drugs by secreting an array of factors, including TGFβ, which induce proliferating cells to exit mitosis and become quiescent-a state that also resists spindle inhibitors. Targeting STAT3 restores sensitivity to each of these drugs by depleting the senescent subpopulation and inducing quiescent cells to enter the mitotic cycle. These results support a therapeutic strategy of targeting STAT3-dependent therapy-induced senescence to enhance the efficacy of spindle inhibitors for the treatment of glioblastoma.
    Highlights: • Resistance to non-microtubule spindle inhibitors limits their efficacy in glioblastoma and depends on STAT3.• Resistance goes hand in hand with development of therapy induced senescence (TIS).• Spindle inhibitor resistant glioblastomas consist of three cell subpopulations-proliferative, quiescent, and TIS-with proliferative cells sensitive and quiescent and TIS cells resistant.• TIS cells secrete TGFβ, which induces proliferative cells to become quiescent, thereby expanding the population of resistant cells in a spindle inhibitor resistant glioblastoma• Treatment with a STAT3 inhibitor kills TIS cells and restores sensitivity to spindle inhibitors.
    DOI:  https://doi.org/10.1101/2024.06.09.598115
  9. bioRxiv. 2024 Apr 27. pii: 2024.04.26.591321. [Epub ahead of print]
    Targeting the sphingolipid rheostat in IDH1 mut glioma alters cholesterol homeostasis and triggers apoptosis via membrane degradation.
    Tyrone Dowdy, Helena Muley Vilamu, Adrian Lita, Aiguo Li, Tomohiro Yamasaki, Lumin Zhang, Raj Chari, Hua Song, Meili Zhang, Wei Zhang, Nicole Briceno, Dionne Davis, Mark R Gilbert, Mioara Larion.
      The cross-regulation of metabolism and trafficking is not well understood for the vital sphingolipids and cholesterol constituents of cellular compartments. While reports are starting to surface on how sphingolipids like sphingomyelin (SM) dysregulate cholesterol levels in different cellular compartments (Jiang et al., 2022), limited research is available on the mechanisms driving the relationship between sphingolipids and cholesterol homeostasis, or its biological implications. Previously, we have identified sphingolipid metabolism as a unique vulnerability for IDH1 mut gliomas via a rational drug design. Herein, we show how modulating sphingolipid levels affects cholesterol homeostasis in brain tumors. However, we unexpectedly discovered for the first time that C17 sphingosine and NDMS addition to cancer cells alters cholesterol homeostasis by impacting its cellular synthesis, uptake, and efflux leading to a net decrease in cholesterol levels and inducing apoptosis. Our results reflect a reverse correlation between the levels of sphingosines, NDMS, and unesterified, free cholesterol in the cells. We show that increasing sphingosine and NDMS (a sphingosine analog) levels alter not only the trafficking of cholesterol between membranes but also the efflux and synthesis of cholesterol. We also demonstrate that despite the effort to remove free cholesterol by ABCA1-mediated efflux or by suppressing machinery for the influx (LDLR) and biosynthetic pathway (HMGCR), apoptosis is inevitable for IDH1 mut glioma cells. This is the first study that shows how altering sphingosine levels directly affects cholesterol homeostasis in cancer cells and can be used to manipulate this relationship to induce apoptosis in IDH1 mut gliomas.
    DOI:  https://doi.org/10.1101/2024.04.26.591321
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