bims-malgli 2024-12-15 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2024–12–15
thirteen papers selected by
Oltea Sampetrean, Keio University

The novel DNA cross-linking agent KL-50 is active against patient-derived models of new and recurrent post-temozolomide mismatch repair-deficient glioblastoma.
Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host.
Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma.
Ion channel modulator DPI-201-106 significantly enhances antitumor activity of DNA damage response inhibitors in glioblastoma.
Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing.
O-GlcNAcylation stabilized WTAP promotes GBM malignant progression in an N6-methyladenosine-dependent manner.
Magnetic resonance imaging and o-(2-[18F]fluoroethyl)-l-tyrosine positron emission tomography for early response assessment of nivolumab and bevacizumab in patients with recurrent high-grade astrocytic glioma.
Machine Learning-based Prognostic Subgrouping of Glioblastoma: A Multi-center Study.
A pathologist's guide for the diagnostic workup of paediatric central nervous system tumours.
Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy.
Pleiotropic tumor suppressive functions of PTEN missense mutations during gliomagenesis.
Stressing the importance of circadian time in treatment responses.
Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis.

Neuro Oncol. 2024 Dec 10. pii: noae257. [Epub ahead of print]

The novel DNA cross-linking agent KL-50 is active against patient-derived models of new and recurrent post-temozolomide mismatch repair-deficient glioblastoma.

Matthew McCord, Thomas Sears, Wenxia Wang, Rahul Chaliparambil, Shejuan An, Jann Sarkaria, C David James, Bruce Ruggeri, Susan Gueble, Ranjit Bindra, Craig Horbinski.

   BACKGROUND: Acquired resistance to temozolomide (TMZ) chemotherapy due to DNA mismatch repair (MMR) enzyme deficiency is a barrier to improving outcomes for IDH wild-type glioblastoma (GBM) patients. KL-50 is a new imidazotetrazine-based therapeutic designed to induce DNA interstrand cross links, and subsequent double-stranded breaks, in an MMR-independent manner in cells with O-6-Methylguanine-DNA Methyltransferase (MGMT) deficiency. Previous research showed its efficacy against LN229 glioma cells with MMR and MGMT knockdown. Its activity against patient-derived GBM that model post-TMZ recurrent tumors is unclear.
METHODS: We created MMR-deficient GBM patient-derived xenografts through exposure to TMZ, followed by treatment with additional TMZ or KL-50. We also generated isogenic, MSH6 knockout patient-derived GBM and tested them for sensitivity to TMZ and KL-50.
RESULTS: KL-50 extended the median survival of mice intracranially engrafted with either patient-derived TMZ-naïve GBM6 or TMZ-naïve GBM12 by 1.75-fold and 2.15-fold, respectively (p<0.0001). A low dose (4 Gy) of fractionated RT further extended the survival of KL-50 treated GBM12 mice (median survival=80 days for RT+ KL-50 vs. 71 days KL-50 alone, P=0.018). KL-50 also extended the median survival of mice engrafted with post-TMZ, MMR-deficient GBM6R-m185 (140 days for KL-50 vs. 37 days for vehicle, p<0.0001). MSH6-KO increased TMZ IC50 for GBM6 and GBM12 cultures by >5-fold and >12-fold for cell death and live cell count outputs, respectively. In contrast, MSH6-KO actually decreased KL-50 IC50 by 10-80%.
CONCLUSION: KL-50-based compounds are a promising new strategy for the treatment of MGMT-deficient, MMR-deficient GBM that recurs after frontline TMZ.

Keywords:  Glioblastoma; KL-50; mismatch repair; recurrent; temozolomide

DOI:  https://doi.org/10.1093/neuonc/noae257
Cancer Cell. 2024 Dec 06. pii: S1535-6108(24)00447-1. [Epub ahead of print]

Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host.

Maria F Gonzalez-Aponte, Anna R Damato, Tatiana Simon, Nigina Aripova, Fabrizio Darby, Myung Sik Jeon, Jingqin Luo, Joshua B Rubin, Erik D Herzog.

  Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis despite aggressive therapy. Here, we hypothesized that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We find daily glucocorticoids promote or suppress GBM growth through glucocorticoid receptor (GR) signaling depending on time of day and the clock genes, Bmal1 and Cry. Blocking circadian signals, like vasoactive intestinal peptide or glucocorticoids, dramatically slows GBM growth and disease progression. Analysis of human GBM samples from The Cancer Genome Atlas (TCGA) shows that high GR expression significantly increases hazard of mortality. Finally, mouse and human GBM models have intrinsic circadian rhythms in clock gene expression in vitro and in vivo that entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status. We conclude that GBM entrains to the circadian circuit of the brain, modulating its growth through clock-controlled cues, like glucocorticoids.

Keywords:  Bmal1; TMZ; VIP; cancer neuroscience; circadian rhythms; clock genes; dexamethasone; glioblastoma; glucocorticoids; period gene; temozolomide; vasoactive intestinal peptide

DOI:  https://doi.org/10.1016/j.ccell.2024.11.012
bioRxiv. 2024 Nov 21. pii: 2024.11.20.624542. [Epub ahead of print]

Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma.

Navyateja Korimerla, Baharan Meghdadi, Isra Haq, Kari Wilder-Romans, Jie Xu, Nicole Becker, Ziqing Zhu, Peter Kalev, Nathan Qi, Charles Evans, Maureen Kachman, Zitong Zhao, Angelica Lin, Andrew J Scott, Alexandra O'Brien, Ayesha Kothari, Peter Sajjakulnukit, Li Zhang, Sravya Palavalasa, Erik R Peterson, Marc L Hyer, Katya Marjon, Taryn Sleger, Meredith A Morgan, Costas A Lyssiotis, Everett M Stone, Sean P Ferris, Theodore S Lawrence, Deepak Nagrath, Weihua Zhou, Daniel R Wahl.

Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance. Here, we find that radiation acutely increases the levels of methionine-related metabolites in a variety of treatment-resistant GBM models. Stable isotope tracing studies further revealed that radiation acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event mediated by the kinases of the DNA damage response. In vivo tumor SAM synthesis increases after radiation, while normal brain SAM production remains unchanged, indicating a tumor- specific metabolic alteration to radiation. Pharmacological and dietary strategies to block methionine to SAM conversion slowed DNA damage response and increased cell death following radiation in vitro. Mechanistically, these effects are due to depletion of DNA repair proteins and are reversed by SAM supplementation. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase. Pharmacological inhibition of SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with radiation. By contrast, methionine depletion does not reduce tumor SAM levels and fails to radiosensitize intracranial models, indicating depleting SAM, as opposed to simply lowering methionine, is critical for hindering tumor growth in intracranial models of GBM. These results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo . Inhibiting radiation-induced SAM synthesis slows DNA repair and augments radiation efficacy in GBM. Using MAT2A inhibitors to deplete SAM may selectively overcome treatment resistance in GBMs with defective methionine salvage while sparing normal brain.

DOI: https://doi.org/10.1101/2024.11.20.624542
Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae187

Ion channel modulator DPI-201-106 significantly enhances antitumor activity of DNA damage response inhibitors in glioblastoma.

Brittany Dewdney, Panimaya Jeffreena Miranda, Mani Kuchibhotla, Ranjith Palanisamy, Caitlyn Richworth, Carol J Milligan, Zi Ying Ng, Lauren Ursich, Steve Petrou, Emily V Fletcher, Roger J Daly, Terry C C Lim Kam Sian, Santosh Valvi, Raelene Endersby, Terrance G Johns.

   Background: Glioblastoma, a lethal high-grade glioma, has not seen improvements in clinical outcomes in nearly 30 years. Ion channels are increasingly associated with tumorigenesis, and there are hundreds of brain-penetrant drugs that inhibit ion channels, representing an untapped therapeutic resource. The aim of this exploratory drug study was to screen an ion channel drug library against patient-derived glioblastoma cells to identify new treatments for brain cancer.
Methods: Seventy-two ion channel inhibitors were screened in patient-derived glioblastoma cells, and cell viability was determined using the ViaLight Assay. Cell cycle and apoptosis analysis were determined with flow cytometry using PI and Annexin V staining, respectively. Protein and phosphoprotein expression was determined using mass spectrometry and analyzed using gene set enrichment analysis. Kaplan-Meier survival analyses were performed using intracranial xenograft models of GBM6 and WK1 cells.
Results: The voltage-gated sodium channel modulator, DPI-201-106, was revealed to reduce glioblastoma cell viability in vitro by inducing cell cycle arrest and apoptosis. Phosphoproteomics indicated that DPI-201-106 may impact DNA damage response (DDR) pathways. Combination treatment of DPI-201-106 with the CHK1 inhibitor prexasertib or the PARP inhibitor niraparib demonstrated synergistic effects in multiple patient-derived glioblastoma cells both in vitro and in intracranial xenograft mouse models, extending survival of glioblastoma-bearing mice.
Conclusions: DPI-201-106 enhances the efficacy of DDR inhibitors to reduce glioblastoma growth. As these drugs have already been clinically tested in humans, repurposing DPI-201-106 in novel combinatorial approaches will allow for rapid translation into the clinic.

Keywords:  DNA damage; cell cycle; glioblastoma; ion channel

DOI:  https://doi.org/10.1093/noajnl/vdae187
Cell. 2024 Dec 03. pii: S0092-8674(24)01276-5. [Epub ahead of print]

Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing.

Svenja K Tetzlaff, Ekin Reyhan, Nikolas Layer, C Peter Bengtson, Alina Heuer, Julian Schroers, Anton J Faymonville, Atefeh Pourkhalili Langeroudi, Nina Drewa, Elijah Keifert, Julia Wagner, Stella J Soyka, Marc C Schubert, Nirosan Sivapalan, Rangel L Pramatarov, Verena Buchert, Tim Wageringel, Elena Grabis, Niklas Wißmann, Obada T Alhalabi, Michael Botz, Jovana Bojcevski, Joaquín Campos, Berin Boztepe, Jonas G Scheck, Sascha Henry Conic, Maria C Puschhof, Giulia Villa, Richard Drexler, Yahya Zghaibeh, Fabian Hausmann, Sonja Hänzelmann, Matthia A Karreman, Felix T Kurz, Manuel Schröter, Marc Thier, Abigail K Suwala, Karin Forsberg-Nilsson, Claudio Acuna, Julio Saez-Rodriguez, Amir Abdollahi, Felix Sahm, Michael O Breckwoldt, Bogdana Suchorska, Franz L Ricklefs, Dieter Henrik Heiland, Varun Venkataramani.

  Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain, engaging in widespread functional communication, with cholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor-cell-state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasiveness. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.

Keywords:  brain tumor networks; brain tumors; cancer neuroscience; glioblastoma; invasion; neuron-to-glioma synapse; retrograde tracing; therapeutic rabies virus; therapeutic resistance

DOI:  https://doi.org/10.1016/j.cell.2024.11.002
Neuro Oncol. 2024 Dec 13. pii: noae268. [Epub ahead of print]

O-GlcNAcylation stabilized WTAP promotes GBM malignant progression in an N6-methyladenosine-dependent manner.

Jiawei Qiu, Rongrong Zhao, Caizhi Ma, Qingtong Wang, Boyan Li, Yanhua Qi, Ziwen Pan, Shulin Zhao, Shaobo Wang, Zijie Gao, Xiaofan Guo, Wei Qiu, Weijie Tang, Xing Guo, Lin Deng, Hao Xue, Gang Li.

   BACKGROUND: Interactions between mesenchymal glioblastoma stem cells (MES GSCs) and myeloid-derived macrophages (MDMs) shape the tumor-immunosuppressive microenvironment (TIME), promoting the progression of glioblastoma (GBM). N6-methyladenosine (m6A) plays important roles in the tumor progression. However, the mechanism of m6A in shaping the TIME of GBM remains elusive.
METHODS: Single-cell RNA sequencing and bulk RNA-seq datasets were employed to identify the critical role of WTAP in interactions between MES GBM and MDMs. The biological function of WTAP was confirmed both in vitro and in vivo. Mechanistically, mass spectrum, RNA immunoprecipitation (RIP), and co-immunoprecipitation assays were conducted.
RESULTS: Here, we identified that m6A methyltransferase Wilms' Tumor 1-Associated Protein (WTAP), whose protein stability could be synergistically enhanced via OGT-mediated O-GlcNAcylation and USP7-mediated de-ubiquitination, promoted LOXL2 m6A modification to enhance its mRNA stabilization in an IGF2BP2-dependent manner, upregulating secretion of LOXL2 protein (sLOXL2). sLOXL2 then interacted with integrin α5β1 on GSCs to activate FAK-ERK signaling, inducing mesenchymal transition of GSCs in an autocrine manner. Meanwhile, sLOXL2 also activated the integrin α5β1-FAK-ERK axis in MDMs, which promoted M2-like MDM phenotypes in a paracrine pathway, thereby contributing to T cell exhaustion to induce GBM immune escape. In translational medicine, combinations of the OGT inhibitor by targeting WTAP expression and the LOXL2 antagonist by disrupting MES GSC and MDM interactions showed favorable outcomes to the anti-PD1 immunotherapy.
CONCLUSIONS: WTAP plays critical roles in mesenchymal transition of GSCs and formation of TIME, highlighting the therapeutic potential of targeting WTAP and its downstream effectors to enhance the efficacy of immunotherapy.

Keywords:  Glioblastoma; WTAP; immunotherapy; m6A; tumor-immunosuppressive microenvironment

DOI:  https://doi.org/10.1093/neuonc/noae268
Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae178

Magnetic resonance imaging and o-(2-[18F]fluoroethyl)-l-tyrosine positron emission tomography for early response assessment of nivolumab and bevacizumab in patients with recurrent high-grade astrocytic glioma.

Otto Mølby Henriksen, Simone Maarup, Benedikte Hasselbalch, Hans Skovgaard Poulsen, Ib Jarle Christensen, Karine Madsen, Vibeke Andrée Larsen, Ulrik Lassen, Ian Law.

   Background: In the present study, early response assessment by o-(2-[18F]fluoroethyl)-l-tyrosine (FET) positron emission tomography (PET) and contrast-enhanced magnetic resonance imaging (MRI) were investigated in a phase II open-label single-center study of nivolumab plus bevacizumab for recurrent high-grade astrocytic glioma.
Methods: Twenty patients with nonresectable first recurrence of high-grade astrocytic glioma after EORTC/NCIC protocol underwent [18F]FET PET/MRI at baseline and after 2 cycles of treatment. Whole brain values of contrast-enhancing volume on MRI (CEV), of the mean (TBRmean) and maximal tumor-to-background ratio (TBRmax), and of metabolically active volume (MTV) on [18F]FET PET were obtained. Regional changes in [18F]FET uptake were assessed by parametric response mapping (PRM). Prediction of overall survival (OS) and response (OS > 11 months) were assessed by Cox and receiver operating characteristic (ROC) analysis, respectively. Also, MRI (response assessment in neuro-oncology [RANO] 2.0) and PET-based (PET RANO 1.0) response assessment criteria were compared.
Results: In ROC analysis responders were separated (P < .05) from nonresponders by lower MTV at follow-up (AUC 0.771, cutoff 18.3 mL), larger decrease in MTV (AUC 0.757, cutoff -5.3 mL), larger decrease in both TBRmax (AUC 0.814, cutoff -0.53) and relative TBRmax (AUC 0.829, cutoff -11%) and smaller PRM progressive volume (AUC 0.843, cutoff 4.0 mL). Change in CEV did not predict response. RANO 2.0 and PET RANO response assessment criteria had similar and only borderline prognostic values.
Conclusions: The study indicates that [18F]FET PET is superior to contrast-enhanced MRI for early response assessment in patients with recurrent high-grade astrocytic glioma treated with nivolumab and bevacizumab.

Keywords:  antiangiogenic treatment; high-grade astrocytic glioma; immunotherapy; positron emission tomography; response assessment

DOI:  https://doi.org/10.1093/noajnl/vdae178
Neuro Oncol. 2024 Dec 12. pii: noae260. [Epub ahead of print]

Machine Learning-based Prognostic Subgrouping of Glioblastoma: A Multi-center Study.

ReSPOND consortium

   BACKGROUND: Glioblastoma is the most aggressive adult primary brain cancer, characterized by significant heterogeneity, posing challenges for patient management, treatment planning, and clinical trial stratification.
METHODS: We developed a highly reproducible, personalized prognostication and clinical subgrouping system using machine learning (ML) on routine clinical data, MRI, and molecular measures from 2,838 demographically diverse patients across 22 institutions and 3 continents. Patients were stratified into favorable, intermediate, and poor prognostic subgroups (I, II, III) using Kaplan-Meier analysis (Cox proportional model and hazard ratios [HR]).
RESULTS: The ML model stratified patients into distinct prognostic subgroups with HRs between subgroups I-II and I-III of 1.62 (95%CI: 1.43-1.84, p<0.001) and 3.48 (95%CI: 2.94-4.11, p<0.001), respectively. Analysis of imaging features revealed several tumor properties contributing unique prognostic value, supporting the feasibility of a generalizable prognostic classification system in a diverse cohort.
CONCLUSIONS: Our ML model demonstrates extensive reproducibility and online accessibility, utilizing routine imaging data rather than complex imaging protocols. This platform offers a unique approach for personalized patient management and clinical trial stratification in glioblastoma.

Keywords:  Glioblastoma; Machine Learning; Prognostic Subgrouping; Survival; mpMRI

DOI:  https://doi.org/10.1093/neuonc/noae260
Pathology. 2024 Nov 12. pii: S0031-3025(24)00290-3. [Epub ahead of print]

A pathologist's guide for the diagnostic workup of paediatric central nervous system tumours.

Colleen E D'Arcy, Cynthia E Hawkins.

  Advances in precision medicine and our understanding of the molecular drivers of central nervous system (CNS) tumorigenesis in children have broadened the scope of diagnostic testing that is required on paediatric CNS tumour samples. The pathologist plays a central role in ensuring that the correct test is ordered, in the integration of test results into the diagnosis and in recognising therapeutic targets to guide targeted treatment planning. The diagnostic and molecular workup of many of the prototypical paediatric CNS tumours differs from that required for adult CNS tumours and can be particularly challenging when tissue is limited. Many paediatric CNS tumours are driven by Rat sarcoma virus (RAS)-mitogen-activated protein kinase (MAPK) pathway or histone alterations, a subset are fusion or single-nucleotide variant (SNV) driven, whereas others require specific molecular subgrouping for treatment planning. This review summarises the clinicopathological and molecular features of some of the more prototypical paediatric CNS tumours and provides a practical guide for the pathologist regarding the molecular workup of paediatric CNS tumours. Common diagnostic dilemmas relevant to the diagnosis of paediatric CNS tumours encountered by the paediatric neuropathologist will be explored, together with some suggested approaches to overcoming these. It is hoped this will aid the pathologist to reach a more accurate and clinically informative diagnosis for paediatric CNS tumours.

Keywords:  DNA methylation profiling; NanoString; diffuse midline glioma; embryonal tumour; molecular testing; next-generation sequencing; paediatric CNS tumour; paediatric high-grade glioma; paediatric low-grade glioma; targeted therapy

DOI:  https://doi.org/10.1016/j.pathol.2024.10.002
Cell Stem Cell. 2024 Dec 04. pii: S1934-5909(24)00409-0. [Epub ahead of print]

Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy.

Meghan Logun, Xin Wang, Yusha Sun, Stephen J Bagley, Nannan Li, Arati Desai, Daniel Y Zhang, MacLean P Nasrallah, Emily Ling-Lin Pai, Bike Su Oner, Gabriela Plesa, Donald Siegel, Zev A Binder, Guo-Li Ming, Hongjun Song, Donald M O'Rourke.

  Patient-derived tumor organoids have been leveraged for disease modeling and preclinical studies but rarely applied in real time to aid with interpretation of patient treatment responses in clinics. We recently demonstrated early efficacy signals in a first-in-human, phase 1 study of dual-targeting chimeric antigen receptor (CAR)-T cells (EGFR-IL13Rα2 CAR-T cells) in patients with recurrent glioblastoma. Here, we analyzed six sets of patient-derived glioblastoma organoids (GBOs) treated concurrently with the same autologous CAR-T cell products as patients in our phase 1 study. We found that CAR-T cell treatment led to target antigen reduction and cytolysis of tumor cells in GBOs, the degree of which correlated with CAR-T cell engraftment detected in patients' cerebrospinal fluid (CSF). Furthermore, cytokine release patterns in GBOs mirrored those in patient CSF samples over time. Our findings highlight a unique trial design and GBOs as a valuable platform for real-time assessment of CAR-T cell bioactivity and insights into immunotherapy efficacy.

Keywords:  CAR-T cell therapy; clinical trial; cytokine; ex vivo; glioblastoma; organoid; patient-derived tumor organoid; real-time correlative

DOI:  https://doi.org/10.1016/j.stem.2024.11.010
iScience. 2024 Dec 20. 27(12): 111278

Pleiotropic tumor suppressive functions of PTEN missense mutations during gliomagenesis.

Hyun Jung Jun, Joao A Paulo, Victoria A Appleman, Tomer M Yaron-Barir, Jared L Johnson, Alan T Yeo, Vaughn A Rogers, Shan Kuang, Hemant Varma, Steven P Gygi, Lloyd C Trotman, Al Charest.

  PTEN plays a crucial role in preventing the development of glioblastoma (GBM), a severe and untreatable brain cancer. In GBM, most PTEN deficiencies are missense mutations that have not been thoroughly examined. Here, we leveraged genetically modified mice and isogenic astrocyte cell cultures to investigate the role of clinically relevant mutations (G36E, L42R, C105F, and R173H) in the development of EGFR-driven GBM. We report that the loss of tumor suppression from these mutants is unrelated to their lipid phosphatase activity and rather relate to elevated localization at the cell membrane. Moreover, expression of these PTEN mutations heightened EGFR activity by sequestering EGFR within endomembranes longer and affected its signaling behavior. Through comprehensive studies on global protein phosphorylation and kinase library analyses in cells with the G36E and L42R PTEN mutations, we identified distinct cancer-promoting pathways activated by EGFR, offering targets for treating GBM with these PTEN alterations.

Keywords:  Cancer; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2024.111278
Cancer Cell. 2024 Nov 26. pii: S1535-6108(24)00439-2. [Epub ahead of print]

Stressing the importance of circadian time in treatment responses.

Katja A Lamia.

Circadian disruption increases cancer risk, but connections between circadian clocks and cancer biology are diverse and depend on tumor type. In this issue of Cancer Cell, Gonzalez-Aponte et al. demonstrate that circadian timing of glucocorticoid exposure affects glioblastoma growth. These findings underscore the importance of timing in designing therapeutic interventions.

DOI: https://doi.org/10.1016/j.ccell.2024.11.004
Cell Metab. 2024 Dec 04. pii: S1550-4131(24)00451-0. [Epub ahead of print]

Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis.

Ruilong Liu, Xuelian Ren, Yae Eun Park, Huixu Feng, Xinlei Sheng, Xiaohan Song, Roya AminiTabrizi, Hardik Shah, Lingting Li, Yu Zhang, Kalil G Abdullah, Sarah Dubois-Coyne, Hening Lin, Philip A Cole, Ralph J DeBerardinis, Samuel K McBrayer, He Huang, Yingming Zhao.

  Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-coenzyme A (CoA) and how this process is regulated remains unknown. Here, we report the identification of guanosine triphosphate (GTP)-specific SCS (GTPSCS) as a lactyl-CoA synthetase in the nucleus. The mechanism was elucidated through the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to elevate histone lactylation but not succinylation. This process depends on a nuclear localization signal in the GTPSCS G1 subunit and acetylation at G2 subunit residue K73, which mediates the interaction with p300. GTPSCS/p300 collaboration synergistically regulates histone H3K18la and GDF15 expression, promoting glioma proliferation and radioresistance. GTPSCS represents the inaugural enzyme to catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression in glioma.

Keywords:  GDF15; histone marks; hypoxia; lactyl-CoA; lactyl-CoA synthetase; lactylation; p300; succinyl-CoA synthetase; the Warburg effect; tumorigenesis

DOI:  https://doi.org/10.1016/j.cmet.2024.11.005