Martina Offi, Lucia Gabriele, Giulia Romagnoli, Liverana Lauretti, Roberto Pallini, Quintino Giorgio D'Alessandris
{"title":"The Sybil prophecy: Searching for predictors of response to bevacizumab in glioblastoma.","authors":"Martina Offi, Lucia Gabriele, Giulia Romagnoli, Liverana Lauretti, Roberto Pallini, Quintino Giorgio D'Alessandris","doi":"10.1093/neuonc/noae088","DOIUrl":"10.1093/neuonc/noae088","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141420098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lisa Dobber, Marjolein Geurts, Martin J van den Bent
{"title":"Tumor growth in recurrent glioblastoma-RANO: when to plan the baseline scan?","authors":"Lisa Dobber, Marjolein Geurts, Martin J van den Bent","doi":"10.1093/neuonc/noae095","DOIUrl":"10.1093/neuonc/noae095","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ongoing expansion of journal activities to meet the needs of stakeholders.","authors":"Susan M Chang","doi":"10.1093/neuonc/noae117","DOIUrl":"10.1093/neuonc/noae117","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rifaquat Rahman, Diana D Shi, Zachary J Reitman, Petra Hamerlik, John F de Groot, Daphne A Haas-Kogan, Alan D D'Andrea, Erik P Sulman, Kirk Tanner, Nathalie Y R Agar, Jann N Sarkaria, Christopher L Tinkle, Ranjit S Bindra, Minesh P Mehta, Patrick Y Wen
DNA damage response (DDR) mechanisms are critical to maintenance of overall genomic stability, and their dysfunction can contribute to oncogenesis. Significant advances in our understanding of DDR pathways have raised the possibility of developing therapies that exploit these processes. In this expert-driven consensus review, we examine mechanisms of response to DNA damage, progress in development of DDR inhibitors in IDH-wild-type glioblastoma and IDH-mutant gliomas, and other important considerations such as biomarker development, preclinical models, combination therapies, mechanisms of resistance and clinical trial design considerations.
DNA 损伤应答(DDR)机制是维持基因组整体稳定性的关键,其功能障碍可导致肿瘤发生。我们对 DDR 途径的认识取得了重大进展,这为开发利用这些过程的疗法提供了可能。在这篇专家共识综述中,我们探讨了 DNA 损伤的反应机制、IDH 野生型胶质母细胞瘤和 IDH 突变型胶质瘤中 DDR 抑制剂的开发进展,以及生物标志物开发、临床前模型、联合疗法、耐药机制和临床试验设计注意事项等其他重要考虑因素。
{"title":"DNA damage response in brain tumors: A Society for Neuro-Oncology consensus review on mechanisms and translational efforts in neuro-oncology.","authors":"Rifaquat Rahman, Diana D Shi, Zachary J Reitman, Petra Hamerlik, John F de Groot, Daphne A Haas-Kogan, Alan D D'Andrea, Erik P Sulman, Kirk Tanner, Nathalie Y R Agar, Jann N Sarkaria, Christopher L Tinkle, Ranjit S Bindra, Minesh P Mehta, Patrick Y Wen","doi":"10.1093/neuonc/noae072","DOIUrl":"10.1093/neuonc/noae072","url":null,"abstract":"<p><p>DNA damage response (DDR) mechanisms are critical to maintenance of overall genomic stability, and their dysfunction can contribute to oncogenesis. Significant advances in our understanding of DDR pathways have raised the possibility of developing therapies that exploit these processes. In this expert-driven consensus review, we examine mechanisms of response to DNA damage, progress in development of DDR inhibitors in IDH-wild-type glioblastoma and IDH-mutant gliomas, and other important considerations such as biomarker development, preclinical models, combination therapies, mechanisms of resistance and clinical trial design considerations.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Daniel de la Nava, Iker Ausejo-Mauleon, Virginia Laspidea, Marisol Gonzalez-Huarriz, Andrea Lacalle, Noelia Casares, Marta Zalacain, Lucía Marrodan, Marc García-Moure, Maria C Ochoa, Antonio Carlos Tallon-Cobos, Reyes Hernandez-Osuna, Javier Marco-Sanz, Laasya Dhandapani, Irati Hervás-Corpión, Oren J Becher, Javad Nazarian, Sabine Mueller, Timothy N Phoenix, Jasper van der Lugt, Mikel Hernaez, Elizabeth Guruceaga, Carl Koschmann, Sriram Venneti, Joshua E Allen, Matthew D Dun, Juan Fueyo, Candelaria Gomez-Manzano, Jaime Gallego Perez-Larraya, Ana Patiño-García, Sara Labiano, Marta M Alonso
Background: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.
Methods: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the efficacy of the combination in vivo. The tumor immune microenvironment was evaluated using flow cytometry, RNAseq, and multiplexed immunofluorescence staining.
Results: The Delta-24-RGD/ONC201 combination did not affect the virus replication capability in human pHGG and DMG models in vitro. Cytotoxicity analysis showed that the combination treatment was either synergistic or additive. Mechanistically, the combination treatment increased nuclear DNA damage and maintained the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extended the overall survival of mice implanted with human and murine pHGG and DMG cells, independent of H3 mutation status and location. Finally, combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment to a proinflammatory phenotype.
Conclusions: The Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone in in vitro and in vivo models by potentiating nuclear DNA damage and in turn improving the antitumor (immune) response to each agent alone.
背景:小儿高级别胶质瘤(pHGGs),包括弥漫中线胶质瘤(DMGs),是预后最差的侵袭性小儿肿瘤之一。Delta-24-RGD和ONC201作为单药对这些肿瘤显示出良好的疗效。然而,这两种药物的联合应用尚未进行评估:方法:通过免疫印迹和复制试验评估功能性病毒的产生。方法:通过免疫印迹和复制试验评估了功能性病毒的产生,并在一组人类和鼠类 pHGG 和 DMG 细胞系中评估了抗肿瘤效果。RNAseq、海马压力测试、线粒体DNA含量和γH2A.X免疫荧光被用来进行机理研究。使用这两种疾病的小鼠模型来评估组合药物在体内的疗效。使用流式细胞术、RNAseq和多重免疫荧光染色对肿瘤免疫微环境进行了评估:结果:Delta-24-RGD/ONC201组合物在体外并不影响人类pHGG和DMG模型的病毒复制能力。细胞毒性分析表明,联合治疗具有协同或相加作用。从机理上讲,联合治疗增加了核 DNA 损伤,并维持了每种药剂单独造成的代谢扰动和线粒体损伤。Delta-24-RGD/ONC201联合治疗可延长植入人和小鼠pHGG和DMG细胞的小鼠的总存活时间,与H3突变状态和位置无关。最后,在小鼠DMG模型中进行的联合治疗显示,肿瘤微环境重塑为一种促炎表型:结论:在体外和体内模型中,Delta-24-RGD/ONC201联合疗法通过增强核DNA损伤提高了疗效,进而改善了单独使用每种药物的抗肿瘤(免疫)反应。
{"title":"The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models.","authors":"Daniel de la Nava, Iker Ausejo-Mauleon, Virginia Laspidea, Marisol Gonzalez-Huarriz, Andrea Lacalle, Noelia Casares, Marta Zalacain, Lucía Marrodan, Marc García-Moure, Maria C Ochoa, Antonio Carlos Tallon-Cobos, Reyes Hernandez-Osuna, Javier Marco-Sanz, Laasya Dhandapani, Irati Hervás-Corpión, Oren J Becher, Javad Nazarian, Sabine Mueller, Timothy N Phoenix, Jasper van der Lugt, Mikel Hernaez, Elizabeth Guruceaga, Carl Koschmann, Sriram Venneti, Joshua E Allen, Matthew D Dun, Juan Fueyo, Candelaria Gomez-Manzano, Jaime Gallego Perez-Larraya, Ana Patiño-García, Sara Labiano, Marta M Alonso","doi":"10.1093/neuonc/noae066","DOIUrl":"10.1093/neuonc/noae066","url":null,"abstract":"<p><strong>Background: </strong>Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.</p><p><strong>Methods: </strong>The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the efficacy of the combination in vivo. The tumor immune microenvironment was evaluated using flow cytometry, RNAseq, and multiplexed immunofluorescence staining.</p><p><strong>Results: </strong>The Delta-24-RGD/ONC201 combination did not affect the virus replication capability in human pHGG and DMG models in vitro. Cytotoxicity analysis showed that the combination treatment was either synergistic or additive. Mechanistically, the combination treatment increased nuclear DNA damage and maintained the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extended the overall survival of mice implanted with human and murine pHGG and DMG cells, independent of H3 mutation status and location. Finally, combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment to a proinflammatory phenotype.</p><p><strong>Conclusions: </strong>The Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone in in vitro and in vivo models by potentiating nuclear DNA damage and in turn improving the antitumor (immune) response to each agent alone.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140330001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Unraveling the hypoxic puzzle: LncRNA LUCAT1 drives glioblastoma in cooperation with HIF1α.","authors":"Ying Zhang, Kadie Hudson, Roger Abounader","doi":"10.1093/neuonc/noae096","DOIUrl":"10.1093/neuonc/noae096","url":null,"abstract":"","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Patricia O'Hare, Tabitha Cooney, Peter de Blank, David H Gutmann, Mark Kieran, Till Milde, Jason Fangusaro, Michael Fisher, Shivaram Avula, Roger Packer, Kohei Fukuoka, Kshitij Mankad, Sabine Mueller, Angela J Waanders, Enrico Opocher, Eric Bouffet, Eric Raabe, Natacha Entz Werle, Amedeo A Azizi, Nathan J Robison, Pablo Hernáiz Driever, Mark Russo, Netteke Schouten, Cornelis M van Tilburg, Astrid Sehested, Jacques Grill, Pratiti Bandopadhayay, John-Paul Kilday, Olaf Witt, David M Ashley, Birgit Betina Ertl-Wagner, Uri Tabori, Darren R Hargrave
Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor group. The natural history, when curative resection is not possible, is one of a chronic disease with periods of tumor stability and episodes of tumor progression. While there is a high overall survival rate, many patients experience significant and potentially lifelong morbidities. The majority of pLGGs have an underlying activation of the RAS/MAPK pathway due to mutational events, leading to the use of molecularly targeted therapies in clinical trials, with recent regulatory approval for the combination of BRAF and MEK inhibition for BRAFV600E mutated pLGG. Despite encouraging activity, tumor regrowth can occur during therapy due to drug resistance, off treatment as tumor recurrence, or as reported in some patients as a rapid rebound growth within 3 months of discontinuing targeted therapy. Definitions of these patterns of regrowth have not been well described in pLGG. For this reason, the International Pediatric Low-Grade Glioma Coalition, a global group of physicians and scientists, formed the Resistance, Rebound, and Recurrence (R3) working group to study resistance, rebound, and recurrence. A modified Delphi approach was undertaken to produce consensus-based definitions and recommendations for regrowth patterns in pLGG with specific reference to targeted therapies.
{"title":"Resistance, rebound, and recurrence regrowth patterns in pediatric low-grade glioma treated by MAPK inhibition: A modified Delphi approach to build international consensus-based definitions-International Pediatric Low-Grade Glioma Coalition.","authors":"Patricia O'Hare, Tabitha Cooney, Peter de Blank, David H Gutmann, Mark Kieran, Till Milde, Jason Fangusaro, Michael Fisher, Shivaram Avula, Roger Packer, Kohei Fukuoka, Kshitij Mankad, Sabine Mueller, Angela J Waanders, Enrico Opocher, Eric Bouffet, Eric Raabe, Natacha Entz Werle, Amedeo A Azizi, Nathan J Robison, Pablo Hernáiz Driever, Mark Russo, Netteke Schouten, Cornelis M van Tilburg, Astrid Sehested, Jacques Grill, Pratiti Bandopadhayay, John-Paul Kilday, Olaf Witt, David M Ashley, Birgit Betina Ertl-Wagner, Uri Tabori, Darren R Hargrave","doi":"10.1093/neuonc/noae074","DOIUrl":"10.1093/neuonc/noae074","url":null,"abstract":"<p><p>Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor group. The natural history, when curative resection is not possible, is one of a chronic disease with periods of tumor stability and episodes of tumor progression. While there is a high overall survival rate, many patients experience significant and potentially lifelong morbidities. The majority of pLGGs have an underlying activation of the RAS/MAPK pathway due to mutational events, leading to the use of molecularly targeted therapies in clinical trials, with recent regulatory approval for the combination of BRAF and MEK inhibition for BRAFV600E mutated pLGG. Despite encouraging activity, tumor regrowth can occur during therapy due to drug resistance, off treatment as tumor recurrence, or as reported in some patients as a rapid rebound growth within 3 months of discontinuing targeted therapy. Definitions of these patterns of regrowth have not been well described in pLGG. For this reason, the International Pediatric Low-Grade Glioma Coalition, a global group of physicians and scientists, formed the Resistance, Rebound, and Recurrence (R3) working group to study resistance, rebound, and recurrence. A modified Delphi approach was undertaken to produce consensus-based definitions and recommendations for regrowth patterns in pLGG with specific reference to targeted therapies.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140922773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Hypoxia is a pathological hallmark in most cancers, including glioblastoma (GBM). Hypoxic signaling activation and post-translational modification (PTM) of oncogenic proteins are well-studied in cancers. Accumulating studies indicate glycolytic enzyme PGK1 plays a crucial role in tumorigenesis, yet the underlying mechanisms remain unknown.
Methods: We first used ChIP assays to uncover the crosstalk between HIF1α and ATF3 and their roles in P4HA1 regulation. Protein degradation analysis, LC-MS/MS, and in vitro succinate production assays were performed to examine the effect of protein succinylation on GBM pathology. Seahorse assay measured the effects of PGK1 succinylation at K191/K192 or its mutants on glucose metabolism. We utilized an in vivo intracranial mouse model for biochemical studies to elucidate the impact of ATF3 and P4HA1 on aerobic glycolysis and the tumor immune microenvironment.
Results: We demonstrated that HIF1α and ATF3 positively and negatively regulate the transcription of P4HA1, respectively, leading to an increased succinate production and increased activation of HIF1α signaling. P4HA1 expression elevated the succinate concentration, resulting in the enhanced succinylation of PGK1 at the K191 and K192 sites. Inhibition of proteasomal degradation of PGK1 by succinylation significantly increased aerobic glycolysis to generate lactate. Furthermore, ATF3 overexpression and P4HA1 knockdown reduced succinate and lactate levels in GBM cells, inhibiting immune responses and tumor growth.
Conclusions: Together, our study demonstrates that HIF1α/ATF3 participated in P4HA1/succinate signaling, which is the major regulator of succinate biosynthesis and PGK1 succinylation at K191 and K192 sites in GBM. The P4HA1/succinate pathway might be a novel and promising target for aerobic glycolysis in GBM.
{"title":"HIF1α/ATF3 partake in PGK1 K191/K192 succinylation by modulating P4HA1/succinate signaling in glioblastoma.","authors":"Shixue Yang, Qi Zhan, Dongyuan Su, Xiaoteng Cui, Jixing Zhao, Qixue Wang, Biao Hong, Jiasheng Ju, Chunchao Cheng, Eryan Yang, Chunsheng Kang","doi":"10.1093/neuonc/noae040","DOIUrl":"10.1093/neuonc/noae040","url":null,"abstract":"<p><strong>Background: </strong>Hypoxia is a pathological hallmark in most cancers, including glioblastoma (GBM). Hypoxic signaling activation and post-translational modification (PTM) of oncogenic proteins are well-studied in cancers. Accumulating studies indicate glycolytic enzyme PGK1 plays a crucial role in tumorigenesis, yet the underlying mechanisms remain unknown.</p><p><strong>Methods: </strong>We first used ChIP assays to uncover the crosstalk between HIF1α and ATF3 and their roles in P4HA1 regulation. Protein degradation analysis, LC-MS/MS, and in vitro succinate production assays were performed to examine the effect of protein succinylation on GBM pathology. Seahorse assay measured the effects of PGK1 succinylation at K191/K192 or its mutants on glucose metabolism. We utilized an in vivo intracranial mouse model for biochemical studies to elucidate the impact of ATF3 and P4HA1 on aerobic glycolysis and the tumor immune microenvironment.</p><p><strong>Results: </strong>We demonstrated that HIF1α and ATF3 positively and negatively regulate the transcription of P4HA1, respectively, leading to an increased succinate production and increased activation of HIF1α signaling. P4HA1 expression elevated the succinate concentration, resulting in the enhanced succinylation of PGK1 at the K191 and K192 sites. Inhibition of proteasomal degradation of PGK1 by succinylation significantly increased aerobic glycolysis to generate lactate. Furthermore, ATF3 overexpression and P4HA1 knockdown reduced succinate and lactate levels in GBM cells, inhibiting immune responses and tumor growth.</p><p><strong>Conclusions: </strong>Together, our study demonstrates that HIF1α/ATF3 participated in P4HA1/succinate signaling, which is the major regulator of succinate biosynthesis and PGK1 succinylation at K191 and K192 sites in GBM. The P4HA1/succinate pathway might be a novel and promising target for aerobic glycolysis in GBM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140028544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Haidong Huang, Hariti Shah, Jing Hao, Jianhong Lin, Richard A Prayson, Liangqi Xie, Shideng Bao, Abhishek A Chakraborty, Eckhard Jankowsky, Jianjun Zhao, Jennifer S Yu
Background: Hypoxia is associated with poor prognosis in many cancers including glioblastoma (GBM). Glioma stem-like cells (GSCs) often reside in hypoxic regions and serve as reservoirs for disease progression. Long non-coding RNAs (lncRNAs) have been implicated in GBM. However, the lncRNAs that modulate GSC adaptations to hypoxia are poorly understood. Identification of these lncRNAs may provide new therapeutic strategies to target GSCs under hypoxia.
Methods: lncRNAs induced by hypoxia in GSCs were identified by RNA-seq. Lung cancer-associated transcript-1 (LUCAT1) expression was assessed by qPCR, RNA-seq, Northern blot, single molecule FISH in GSCs, and interrogated in IvyGAP, The Cancer Genome Atlas, and CGGA databases. LUCAT1 was depleted by shRNA, CRISPR/Cas9, and CRISPR/Cas13d. RNA-seq, Western blot, immunohistochemistry, co-IP, ChIP, ChIP-seq, RNA immunoprecipitation, and proximity ligation assay were performed to investigate mechanisms of action of LUCAT1. GSC viability, limiting dilution assay, and tumorigenic potential in orthotopic GBM xenograft models were performed to assess the functional consequences of depleting LUCAT1.
Results: A new isoform of Lucat1 is induced by Hypoxia inducible factor 1 alpha (HIF1α) and Nuclear factor erythroid 2-related factor 2 (NRF2) in GSCs under hypoxia. LUCAT1 is highly expressed in hypoxic regions in GBM. Mechanistically, LUCAT1 formed a complex with HIF1α and its co-activator CBP to regulate HIF1α target gene expression and GSC adaptation to hypoxia. Depletion of LUCAT1 impaired GSC self-renewal. Silencing LUCAT1 decreased tumor growth and prolonged mouse survival in GBM xenograft models.
Conclusions: A HIF1α-LUCAT1 axis forms a positive feedback loop to amplify HIF1α signaling in GSCs under hypoxia. LUCAT1 promotes GSC self-renewal and GBM tumor growth. LUCAT1 is a potential therapeutic target in GBM.
{"title":"Long non-coding RNA lung cancer-associated transcript-1 promotes glioblastoma progression by enhancing Hypoxia-inducible factor 1 alpha activity.","authors":"Haidong Huang, Hariti Shah, Jing Hao, Jianhong Lin, Richard A Prayson, Liangqi Xie, Shideng Bao, Abhishek A Chakraborty, Eckhard Jankowsky, Jianjun Zhao, Jennifer S Yu","doi":"10.1093/neuonc/noae036","DOIUrl":"10.1093/neuonc/noae036","url":null,"abstract":"<p><strong>Background: </strong>Hypoxia is associated with poor prognosis in many cancers including glioblastoma (GBM). Glioma stem-like cells (GSCs) often reside in hypoxic regions and serve as reservoirs for disease progression. Long non-coding RNAs (lncRNAs) have been implicated in GBM. However, the lncRNAs that modulate GSC adaptations to hypoxia are poorly understood. Identification of these lncRNAs may provide new therapeutic strategies to target GSCs under hypoxia.</p><p><strong>Methods: </strong>lncRNAs induced by hypoxia in GSCs were identified by RNA-seq. Lung cancer-associated transcript-1 (LUCAT1) expression was assessed by qPCR, RNA-seq, Northern blot, single molecule FISH in GSCs, and interrogated in IvyGAP, The Cancer Genome Atlas, and CGGA databases. LUCAT1 was depleted by shRNA, CRISPR/Cas9, and CRISPR/Cas13d. RNA-seq, Western blot, immunohistochemistry, co-IP, ChIP, ChIP-seq, RNA immunoprecipitation, and proximity ligation assay were performed to investigate mechanisms of action of LUCAT1. GSC viability, limiting dilution assay, and tumorigenic potential in orthotopic GBM xenograft models were performed to assess the functional consequences of depleting LUCAT1.</p><p><strong>Results: </strong>A new isoform of Lucat1 is induced by Hypoxia inducible factor 1 alpha (HIF1α) and Nuclear factor erythroid 2-related factor 2 (NRF2) in GSCs under hypoxia. LUCAT1 is highly expressed in hypoxic regions in GBM. Mechanistically, LUCAT1 formed a complex with HIF1α and its co-activator CBP to regulate HIF1α target gene expression and GSC adaptation to hypoxia. Depletion of LUCAT1 impaired GSC self-renewal. Silencing LUCAT1 decreased tumor growth and prolonged mouse survival in GBM xenograft models.</p><p><strong>Conclusions: </strong>A HIF1α-LUCAT1 axis forms a positive feedback loop to amplify HIF1α signaling in GSCs under hypoxia. LUCAT1 promotes GSC self-renewal and GBM tumor growth. LUCAT1 is a potential therapeutic target in GBM.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140060008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}