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Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation
Wang, Shuai; Huang, Tengfei; Wu, Qiulian; Yuan, Huairui; Wu, Xujia; Yuan, Fanen; Duan, Tingting; Taori, Suchet; Zhao, Yingming; Snyder, Nathaniel W; Placantonakis, Dimitris G; Rich, Jeremy N
Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a "don't eat me" signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.
PMCID:11563687
PMID: 39545414
ISSN: 1558-8238
CID: 5753752
Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation
Wang, Shuai; Huang, Tengfei; Wu, Qiulian; Yuan, Huairui; Wu, Xujia; Yuan, Fanen; Duan, Tingting; Taori, Suchet; Zhao, Yingming; Snyder, Nathaniel W; Placantonakis, Dimitris G; Rich, Jeremy N
Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a "don't eat me" signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.
PMCID:11563687
PMID: 39545414
ISSN: 1558-8238
CID: 5753742
Middle meningeal artery embolization and tranexamic acid therapy for subdural hematoma in a patient with hereditary hemorrhagic telangiectasia: illustrative case
Kushmakov, Robert; Cazorla-Morales, Ilona; Brenner, Keith; Araten, David; Shapiro, Maksim; Raz, Eytan; Placantonakis, Dimitris G
BACKGROUND:Subdural hematoma is a rare manifestation of hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease. Here, the authors present a patient with HHT and a large chronic subdural hematoma, for whom nonsurgical management was pursued. OBSERVATIONS/METHODS:A 49-year-old right-handed male with a history of hypertension and familial HHT presented with complaints of mild confusion and left hemiparesis over several days. Noncontrast head computed tomography images demonstrated a large chronic right hemisphere subdural hematoma compressing the right cerebral hemisphere and causing a 1.3-cm midline shift. Due to concerns about surgical complications arising from hemorrhages of cryptic telangiectasias, the patient was treated conservatively with middle meningeal artery embolization and adjuvant tranexamic acid. There was clinical and radiological resolution several months later. LESSONS/CONCLUSIONS:This case highlights the rarity of a subdural hematoma as a manifestation of HHT and the nonsurgical treatment strategy as a mechanism to avoid hemorrhagic complications of surgical evacuation. https://thejns.org/doi/10.3171/CASE24483.
PMCID:11539288
PMID: 39496155
ISSN: 2694-1902
CID: 5770692
Staged intervention to enable the resection of a large left temporoinsular cystic glioblastoma with language preservation: illustrative case
Donaldson, Hayley; Golub, Danielle; Placantonakis, Dimitris G
BACKGROUND:Resection of glioblastoma (GBM) in eloquent regions depends on functional mapping to limit perioperative neurological morbidity. When neurological deficits preclude reliable mapping, neurosurgeons should explore potential mitigation strategies. The authors present the case of a patient with a large left cystic temporoinsular GBM and aphasia, for whom the authors used intraoperative language mapping and a staged approach to enable safe tumor resection. OBSERVATIONS/METHODS:A 49-year-old female presented with progressive mixed aphasia for 1 month and new-onset right facial droop. Magnetic resonance imaging (MRI) revealed a large, heterogeneously enhancing, left temporoinsular tumor with a significant cystic component. Her aphasia was profound, and resection without reliable language mapping was deemed unsafe. An initial stereotactic tumoral cyst aspiration was performed, which reduced local mass effect and improved her language function. Cyst decompression thereby enabled both task-based functional MRI and intraoperative awake speech mapping, resulting in a safe resection of her GBM. LESSONS/CONCLUSIONS:Safe resection of eloquently localized GBM is compromised when neurological deficits prohibit intraoperative functional mapping. This case demonstrates a mitigation strategy specific to cystic lesions in which an initial-stage stereotactic cyst aspiration is aimed at generating sufficient interval neurological improvement, such that intraoperative functional mapping can be performed during a second-stage resection. https://thejns.org/doi/10.3171/CASE24362.
PMCID:11488367
PMID: 39401457
ISSN: 2694-1902
CID: 5718382
Laser interstitial thermal therapy for new and recurrent meningioma: a prospective and retrospective case series
Chiang, Veronica L; Pugazenthi, Sangami; Leidig, William A; Rodriguez, Analiz; Prabhu, Sujit; Haskell-Mendoza, Aden P; Fecci, Peter E; Placantonakis, Dimitris G; Abram, Steven R; Lega, Bradley; Kim, Albert H
OBJECTIVE:Meningiomas are the most common primary brain tumors in adults and a subset are aggressive lesions resistant to standard therapies. Laser interstitial thermal therapy (LITT) has been successfully applied to other brain tumors, and recent work aims to explore the safety and long-term outcome experiences of LITT for both new and recurrent meningiomas. The authors' objective was to report safety and outcomes data of the largest cohort of LITT-treated meningioma patients to date. METHODS:Eight United States-based hospitals enrolled patients with meningioma in the Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System (LAANTERN) prospective multicenter registry and/or contributed additional retrospective enrollments for this cohort study. Demographic, procedural, safety, and outcomes data were collected and analyzed using standard statistical methods. RESULTS:Twenty adult patients (12 prospective and 8 retrospective) with LITT-targeted meningiomas were accrued. Patients underwent LITT for new (6 patients) and recurrent (14 patients) tumors (ranging from the 1st to 12th recurrence). The 30-day complication rate was 10%. Twenty percent of patients (4/20) had exhausted all other treatment options. Median length of follow-up was 1.3 years. One-third of new (2/6) and one-half of recurrent (7/14) meningiomas had disease progression during follow-up. One-year estimated local control (LC), progression-free survival, and overall survival rates were 55.3%, 48.4%, and 86.3%, respectively. In the 12 patients who had ≥ 91% ablative coverage, 1-year estimated LC was 61.4%. The complication rate was 10% (2/20), with 1 complication being transient and resolving postoperatively. CONCLUSIONS:This cohort study supports the safety of the procedure for this tumor type. LITT can offer a much-needed treatment option, especially for patients with multiply recurrent meningiomas who have limited remaining alternatives.
PMID: 38457795
ISSN: 1933-0693
CID: 5687022
T2-FLAIR mismatch sign predicts DNA methylation subclass and CDKN2A/B status in IDH-mutant astrocytomas
Lee, Matthew D; Jain, Rajan; Galbraith, Kristyn; Chen, Anna; Lieberman, Evan; Patel, Sohil H; Placantonakis, Dimitris G; Zagzag, David; Barbaro, Marissa; Guillermo Prieto Eibl, Maria Del Pilar; Golfinos, John G; Orringer, Daniel A; Snuderl, Matija
PURPOSE/OBJECTIVE:DNA methylation profiling stratifies isocitrate dehydrogenase (IDH)-mutant astrocytomas into methylation low-grade and high-grade groups. We investigated the utility of the T2-FLAIR mismatch sign for predicting DNA methylation grade and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion, a molecular biomarker for grade 4 IDH-mutant astrocytomas, according to the 2021 World Health Organization (WHO) classification. EXPERIMENTAL DESIGN/METHODS:Preoperative MRI scans of IDH-mutant astrocytomas subclassified by DNA methylation profiling (n=71) were independently evaluated by two radiologists for the T2-FLAIR mismatch sign. The diagnostic utility of T2-FLAIR mismatch in predicting methylation grade, CDKN2A/B status, copy number variation, and survival was analyzed. RESULTS:The T2-FLAIR mismatch sign was present in 21 of 45 (46.7%) methylation low-grade and 1 of 26 (3.9%) methylation high-grade cases (p<0.001), resulting in 96.2% specificity, 95.5% positive predictive value, and 51.0% negative predictive value for predicting low methylation grade. The T2-FLAIR mismatch sign was also significantly associated with intact CDKN2A/B status (p=0.028) with 87.5% specificity, 86.4% positive predictive value, and 42.9% negative predictive value. Overall multivariable Cox analysis showed that retained CDKN2A/B status remained significant for PFS (p=0.01). Multivariable Cox analysis of the histologic grade 3 subset, which was nearly evenly divided by CDKN2A/B status, CNV, and methylation grade, showed trends toward significance for DNA methylation grade with OS (p=0.045) and CDKN2A/B status with PFS (p=0.052). CONCLUSIONS:The T2-FLAIR mismatch sign is highly specific for low methylation grade and intact CDKN2A/B in IDH-mutant astrocytomas.
PMID: 38829583
ISSN: 1557-3265
CID: 5664982
Prognostic value of DNA methylation subclassification, aneuploidy, and CDKN2A/B homozygous deletion in predicting clinical outcome of IDH mutant astrocytomas
Galbraith, Kristyn; Garcia, Mekka; Wei, Siyu; Chen, Anna; Schroff, Chanel; Serrano, Jonathan; Pacione, Donato; Placantonakis, Dimitris G; William, Christopher M; Faustin, Arline; Zagzag, David; Barbaro, Marissa; Eibl, Maria Del Pilar Guillermo Prieto; Shirahata, Mitsuaki; Reuss, David; Tran, Quynh T; Alom, Zahangir; von Deimling, Andreas; Orr, Brent A; Sulman, Erik P; Golfinos, John G; Orringer, Daniel A; Jain, Rajan; Lieberman, Evan; Feng, Yang; Snuderl, Matija
BACKGROUND:Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma. METHODS:We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts. RESULTS:There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534). CONCLUSIONS:The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.
PMCID:11145445
PMID: 38243818
ISSN: 1523-5866
CID: 5664582
Localization of protoporphyrin IX during glioma-resection surgery via paired stimulated Raman histology and fluorescence microscopy
Nasir-Moin, Mustafa; Wadiura, Lisa Irina; Sacalean, Vlad; Juros, Devin; Movahed-Ezazi, Misha; Lock, Emily K; Smith, Andrew; Lee, Matthew; Weiss, Hannah; Müther, Michael; Alber, Daniel; Ratna, Sujay; Fang, Camila; Suero-Molina, Eric; Hellwig, Sönke; Stummer, Walter; Rössler, Karl; Hainfellner, Johannes A; Widhalm, Georg; Kiesel, Barbara; Reichert, David; Mischkulnig, Mario; Jain, Rajan; Straehle, Jakob; Neidert, Nicolas; Schnell, Oliver; Beck, Jürgen; Trautman, Jay; Pastore, Steve; Pacione, Donato; Placantonakis, Dimitris; Oermann, Eric Karl; Golfinos, John G; Hollon, Todd C; Snuderl, Matija; Freudiger, Christian W; Heiland, Dieter Henrik; Orringer, Daniel A
The most widely used fluorophore in glioma-resection surgery, 5-aminolevulinic acid (5-ALA), is thought to cause the selective accumulation of fluorescent protoporphyrin IX (PpIX) in tumour cells. Here we show that the clinical detection of PpIX can be improved via a microscope that performs paired stimulated Raman histology and two-photon excitation fluorescence microscopy (TPEF). We validated the technique in fresh tumour specimens from 115 patients with high-grade gliomas across four medical institutions. We found a weak negative correlation between tissue cellularity and the fluorescence intensity of PpIX across all imaged specimens. Semi-supervised clustering of the TPEF images revealed five distinct patterns of PpIX fluorescence, and spatial transcriptomic analyses of the imaged tissue showed that myeloid cells predominate in areas where PpIX accumulates in the intracellular space. Further analysis of external spatially resolved metabolomics, transcriptomics and RNA-sequencing datasets from glioblastoma specimens confirmed that myeloid cells preferentially accumulate and metabolize PpIX. Our findings question 5-ALA-induced fluorescence in glioma cells and show how 5-ALA and TPEF imaging can provide a window into the immune microenvironment of gliomas.
PMID: 38987630
ISSN: 2157-846x
CID: 5699002
Modulation of GPR133 (ADGRD1) signaling by its intracellular interaction partner extended synaptotagmin 1
Stephan, Gabriele; Haddock, Sara; Wang, Shuai; Erdjument-Bromage, Hediye; Liu, Wenke; Ravn-Boess, Niklas; Frenster, Joshua D; Bready, Devin; Cai, Julia; Ronnen, Rebecca; Sabio-Ortiz, Jonathan; Fenyo, David; Neubert, Thomas A; Placantonakis, Dimitris G
GPR133 (ADGRD1) is an adhesion G-protein-coupled receptor that signals through Gαs/cyclic AMP (cAMP) and is required for the growth of glioblastoma (GBM), an aggressive brain malignancy. The regulation of GPR133 signaling is incompletely understood. Here, we use proximity biotinylation proteomics to identify ESYT1, a Ca2+-dependent mediator of endoplasmic reticulum-plasma membrane bridge formation, as an intracellular interactor of GPR133. ESYT1 knockdown or knockout increases GPR133 signaling, while its overexpression has the opposite effect, without altering GPR133 levels in the plasma membrane. The GPR133-ESYT1 interaction requires the Ca2+-sensing C2C domain of ESYT1. Thapsigargin-mediated increases in cytosolic Ca2+ relieve signaling-suppressive effects of ESYT1 by promoting ESYT1-GPR133 dissociation. ESYT1 knockdown or knockout in GBM slows tumor growth, suggesting tumorigenic functions of ESYT1. Our findings demonstrate a mechanism for the modulation of GPR133 signaling by increased cytosolic Ca2+, which reduces the signaling-suppressive interaction between GPR133 and ESYT1 to raise cAMP levels.
PMID: 38758649
ISSN: 2211-1247
CID: 5663132
Improved reconstruction of crossing fibers in the mouse optic pathways with orientation distribution function fingerprinting
Filipiak, Patryk; Sajitha, Thajunnisa A; Shepherd, Timothy M; Clarke, Kamri; Goldman, Hannah; Placantonakis, Dimitris G; Zhang, Jiangyang; Chan, Kevin C; Boada, Fernando E; Baete, Steven H
PURPOSE/OBJECTIVE:The accuracy of diffusion MRI tractography reconstruction decreases in the white matter regions with crossing fibers. The optic pathways in rodents provide a challenging structure to test new diffusion tractography approaches because of the small crossing volume within the optic chiasm and the unbalanced 9:1 proportion between the contra- and ipsilateral neural projections from the retina to the lateral geniculate nucleus, respectively. METHODS: RESULTS:ODF-FP outperformed by over 100% all the tested methods in terms of the ratios between the contra- and ipsilateral segments of the reconstructed optic pathways as well as the spatial overlap between tractography and MEMRI. CONCLUSION/CONCLUSIONS:In this challenging model system, ODF-Fingerprinting reduced uncertainty of diffusion tractography for complex structural formations of fiber bundles.
PMID: 37927121
ISSN: 1522-2594
CID: 5612792