1
|
Kisby T, Borst GR, Coope DJ, Kostarelos K. Targeting the glioblastoma resection margin with locoregional nanotechnologies. Nat Rev Clin Oncol 2025:10.1038/s41571-025-01020-2. [PMID: 40369318 DOI: 10.1038/s41571-025-01020-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2025] [Indexed: 05/16/2025]
Abstract
Surgical resection is the first stage of treatment for patients diagnosed with resectable glioblastoma and is followed by a combination of adjuvant radiotherapy and systemic single-agent chemotherapy, which is typically commenced 4-6 weeks after surgery. This delay creates an interval during which residual tumour cells residing in the resection margin can undergo uninhibited proliferation and further invasion, even immediately after surgery, thus limiting the effectiveness of adjuvant therapies. Recognition of the postsurgical resection margin and peri-marginal zones as important anatomical clinical targets and the need to rethink current strategies can galvanize opportunities for local, intraoperative approaches, while also generating a new landscape of innovative treatment modalities. In this Perspective, we discuss opportunities and challenges for developing locoregional therapeutic strategies to target the glioblastoma resection margin as well as emerging opportunities offered by nanotechnology in this clinically transformative setting. We also discuss how persistent barriers to clinical translation can be overcome to offer a potential path forward towards broader acceptability of such advanced technologies.
Collapse
Affiliation(s)
- Thomas Kisby
- Centre for Nanotechnology in Medicine, Faculty of Biology & Medicine and Health, University of Manchester, Manchester, UK
- Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance NHS Foundation Trust, University of Manchester, Manchester, UK
| | - Gerben R Borst
- Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance NHS Foundation Trust, University of Manchester, Manchester, UK
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health & Manchester Cancer Research Centre, Manchester Academic Health Science Centre (MAHSC), University of Manchester, Manchester, UK
- Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - David J Coope
- Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance NHS Foundation Trust, University of Manchester, Manchester, UK
- Department of Neurosurgery, Manchester Centre for Clinical Neurosciences, Northern Care Alliance NHS Foundation Trust, Salford Royal, Salford, UK
| | - Kostas Kostarelos
- Centre for Nanotechnology in Medicine, Faculty of Biology & Medicine and Health, University of Manchester, Manchester, UK.
- Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance NHS Foundation Trust, University of Manchester, Manchester, UK.
- Nanomedicine Lab, Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST, Barcelona, Spain.
- Institute of Neuroscience, Universitat Autònoma de Barcelona, Barcelona, Spain.
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
| |
Collapse
|
2
|
Mulliqi E, Khelwatty S, Bagwan I, Kamaludin A, Morgan A, Long N, Ashkan K, Modjtahedi H. The Co-Expression and Cellular Location of HER Family Members, EGFRvIII, Putative Cancer Stem Cell Biomarkers CD44 and CD109 in Patients with Glioblastoma, and Their Impacts on Prognosis. Cancers (Basel) 2025; 17:1221. [PMID: 40227788 PMCID: PMC11987930 DOI: 10.3390/cancers17071221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/26/2025] [Accepted: 03/30/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND/OBJECTIVES The aberrant expression and activation of HER family members is a known major oncogenic pathway for the proliferation, progression, and metastasis of a wide range of human malignancies. In this study, our aim was to examine the relative expression and prognostic significance of all members of the HER family, the type III EGFR mutant (EGFRvIII), and the putative stem cell markers CD44 and CD109 in patients with glioblastoma. METHODS The expression levels of wild-type EGFR (wtEGFR), HER2, HER3, HER4, EGFRvIII, CD44, and CD109 were determined in tumour specimens from 80 patients by immunohistochemistry. The staining was scored based on the percentage of positive tumour cells, the intensity, and the cellular location of immunostaining. The association between the expression level of the biomarkers and patient overall survival was evaluated using Chi-squared, Kaplan-Meier survival curves, and log-rank tests. RESULTS At a cut-off value of ≥5% with positive staining, 46% (wtEGFR), 75% (HER2), 19% (HER3), 71% (HER4), 85% (EGFRvIII), 95% (CD44), and 16% (CD109) of the cases were positive for these biomarkers. Interestingly, at the same cut-off value, the expression of wtEGFR in these patients was accompanied by co-expression with HER2 (35%), HER3 (0%), HER4 (30%), EGFRvIII (36%), CD44 (44%), HER2/EGFRvIII (28%), HER2/CD44 (31%), and EGFRvIII/CD44 (36%). In addition, the expression of EGFRvIII was accompanied by co-expression with HER2 (65%), HER3 (15%), HER4 (63%), CD44 (83%), CD109 (16%), wtEGFR/HER2 (28%), and 55% of the cases had co-expression of EGFRvIII/HER2/HER4/CD44. With the exception of HER2 expression, at cut-off values of ≥5% of tumour cells with positive staining, which was associated with better overall survival [HR = 0.57 (p = 0.038), HR = 0.56 (p = 0.034)], there was no significant association between the expression of other members of the HER family, EGFRvIII, CD44, and CD109 on the overall survival in both univariate and multivariate analysis. Conclusions Our results suggest that the co-expression of different members of the HER family, with EGFRvIII, CD44, and CD109, occurs in patients with glioblastoma. As the results of therapy with EGFR inhibitors have not been encouraging in patients with a brain tumour, further investigation should determine whether the co-expression of such biomarkers can be of predictive value for the response to the therapy with various types of HER inhibitors and their potential as therapeutic targets for co-targeted therapy.
Collapse
Affiliation(s)
- Ermira Mulliqi
- School of Life Science, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston-upon-Thames KT1 2EE, UK; (E.M.); (S.K.); (I.B.); (A.M.)
| | - Said Khelwatty
- School of Life Science, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston-upon-Thames KT1 2EE, UK; (E.M.); (S.K.); (I.B.); (A.M.)
| | - Izhar Bagwan
- School of Life Science, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston-upon-Thames KT1 2EE, UK; (E.M.); (S.K.); (I.B.); (A.M.)
- Berkshire Surrey Pathology Services, Royal Surrey Hospital, Guildford GU2 7XX, UK
| | - Ahmad Kamaludin
- Department of Neurosurgery, Kings College Hospital, Denmark Hill, London SE5 9RS, UK; (A.K.); (N.L.); (K.A.)
| | - Anna Morgan
- School of Life Science, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston-upon-Thames KT1 2EE, UK; (E.M.); (S.K.); (I.B.); (A.M.)
| | - Natalie Long
- Department of Neurosurgery, Kings College Hospital, Denmark Hill, London SE5 9RS, UK; (A.K.); (N.L.); (K.A.)
| | - Keyoumars Ashkan
- Department of Neurosurgery, Kings College Hospital, Denmark Hill, London SE5 9RS, UK; (A.K.); (N.L.); (K.A.)
| | - Helmout Modjtahedi
- School of Life Science, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston-upon-Thames KT1 2EE, UK; (E.M.); (S.K.); (I.B.); (A.M.)
| |
Collapse
|
3
|
Zhou Y, He Q, Huang G, Ouyang P, Wang H, Deng J, Chen P, Liang X, Hong Z, Zhang X, Qi S, Li Y. Malignant Cells Beyond the Tumor Core: The Non-Negligible Factor to Overcome the Refractory of Glioblastoma. CNS Neurosci Ther 2025; 31:e70333. [PMID: 40104956 PMCID: PMC11920816 DOI: 10.1111/cns.70333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/27/2025] [Accepted: 03/01/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Glioblastoma (GBM) is one of the most aggressive primary brain tumors in adults. Over 95% of GBM patients experience recurrence in the peritumoral brain tissue or distant regions, indicating the presence of critical factors in these areas that drive tumor recurrence. Current clinical treatments primarily focus on tumor cells from the tumor core (TC), while the role of neoplastic cells beyond the TC has been largely neglected. METHODS We conducted a comprehensive review of existing literature and studies on GBM, focusing on the identification and characterization of questionable cells (Q cells). Advanced imaging techniques, such as diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET), were utilized to identify Q cells beyond the tumor core. We also analyzed the functional properties, cellular microenvironment, and physical characteristics of Q cells, as well as their implications for surgical resection. RESULTS Our review revealed that Q cells exhibit unique functional attributes, including enhanced invasiveness, metabolic adaptations, and resistance mechanisms. These cells reside in a distinct cellular microenvironment and are influenced by physical properties such as solid stress and stiffness. Advanced imaging techniques have improved the identification of Q cells, enabling more precise surgical resection. Targeting Q cells in therapeutic strategies could significantly reduce the risk of GBM recurrence. CONCLUSION The presence of Q cells in the peritumoral brain zone (PBZ) and beyond is a critical factor in GBM recurrence. Current treatments, which primarily target tumor cells in the TC, are insufficient to prevent recurrence due to the neglect of Q cells. Future research should focus on understanding the mechanisms influencing Q cells and developing targeted therapies to improve patient outcomes.
Collapse
Affiliation(s)
- Yuyang Zhou
- Department of Neurosurgery, Institute of Brain Disease, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Qilin He
- Department of Neurosurgery, Institute of Brain Disease, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Guanglong Huang
- Department of Neurosurgery, Institute of Brain Disease, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Pei Ouyang
- Department of Neurosurgery, Institute of Brain Disease, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Hai Wang
- Department of Neurosurgery, Institute of Brain Disease, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Jiapeng Deng
- Department of Neurosurgery, Institute of Brain Disease, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Pengyu Chen
- Department of Neurosurgery, Institute of Brain Disease, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Xuan Liang
- Department of Neurosurgery, Institute of Brain Disease, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Zhisheng Hong
- Department of Neurosurgery, Institute of Brain Disease, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Xian Zhang
- Department of Neurosurgery, Institute of Brain Disease, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Songtao Qi
- Department of Neurosurgery, Institute of Brain Disease, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Yaomin Li
- Department of Neurosurgery, Institute of Brain Disease, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| |
Collapse
|
4
|
Li Z, Zhang Y, Li D, Du X, Chen L, Guo Y. Microglial upregulation of CD109 expression in spinal cord of amyotrophic lateral sclerosis mouse model and its role in modulating inflammation and TGFβ/SMAD pathway. Neuroscience 2025; 564:202-213. [PMID: 39577687 DOI: 10.1016/j.neuroscience.2024.11.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 11/12/2024] [Accepted: 11/19/2024] [Indexed: 11/24/2024]
Abstract
CD109 is a multifunctional coreceptor, whose function has been widely studied in tumor progression and metastasis. One of the reported primary roles of CD109 involves down-regulating TGFβ signaling. However, the role of CD109 in central nervous system, especially neurodegenerative disease, is barely known. Here, we examined the expression changes and cellular location of CD109 and TGFβ/SMAD pathway molecules in lumbar spinal cord of SOD1-G93A mice, and explored the role and mechanism of CD109 on LPS-treated BV2 microglia and primary microglia derived from SOD1-G93A mice. Our results showed an increased expression of CD109 and TGFβ/SMAD pathway molecules in lumbar spinal cord of SOD1-G93A mice. Further cellular localization analysis demonstrated that proliferating microglia contributed mainly to the upregulation of CD109 and TGFβ1. Moreover, CD109 intervention in vitro partially reduced inflammatory response and TGFβ/SMAD pathway activation in both LPS-treated BV2 microglia and primary SOD1-G93A microglia. Thus, CD109 was involved in pathogenesis of ALS mice, and interventions targeting on CD109 modulation could be a potential therapeutic strategy for ALS.
Collapse
Affiliation(s)
- Zhongzhong Li
- Department of Neurology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Xinhua District, Shijiazhuang 050000, China
| | - Yingzhen Zhang
- Department of Neurology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Xinhua District, Shijiazhuang 050000, China
| | - Dongxiao Li
- Department of Neurology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Xinhua District, Shijiazhuang 050000, China
| | - Xinyan Du
- Beijing Geriatric Healthcare and Disease Prevention Center, Xuanwu Hospital, Capital Medical University, No. 45 Changchun Street, Xicheng District, Beijing 100053, China
| | - Lin Chen
- Department of Neurology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Xinhua District, Shijiazhuang 050000, China
| | - Yansu Guo
- Department of Neurology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Xinhua District, Shijiazhuang 050000, China; Beijing Geriatric Healthcare and Disease Prevention Center, Xuanwu Hospital, Capital Medical University, No. 45 Changchun Street, Xicheng District, Beijing 100053, China; Beijing Municipal Geriatric Medical Research Center, No. 45 Changchun Street, Xicheng District, Beijing 100053, China.
| |
Collapse
|
5
|
Bastola S, Pavlyukov MS, Sharma N, Ghochani Y, Nakano MA, Muthukrishnan SD, Yu SY, Kim MS, Sohrabi A, Biscola NP, Yamashita D, Anufrieva KS, Kovalenko TF, Jung G, Ganz T, O'Brien B, Kawaguchi R, Qin Y, Seidlits SK, Burlingame AL, Oses-Prieto JA, Havton LA, Goldman SA, Hjelmeland AB, Nakano I, Kornblum HI. Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma. Nat Commun 2025; 16:471. [PMID: 39773984 PMCID: PMC11707362 DOI: 10.1038/s41467-024-55487-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Extensive neovascularization is a hallmark of glioblastoma (GBM). In addition to supplying oxygen and nutrients, vascular endothelial cells provide trophic support to GBM cells via paracrine signaling. Here we report that Endocan (ESM1), an endothelial-secreted proteoglycan, confers enhanced proliferative, migratory, and angiogenic properties to GBM cells and regulates their spatial identity. Mechanistically, Endocan exerts at least part of its functions via direct binding and activation of the PDGFRA receptor. Subsequent downstream signaling enhances chromatin accessibility of the Myc promoter and upregulates Myc expression inducing stable phenotypic changes in GBM cells. Furthermore, Endocan confers radioprotection on GBM cells in vitro and in vivo. Inhibition of Endocan-PDGFRA signaling with ponatinib increases survival in the Esm1 wild-type but not in the Esm1 knock-out mouse GBM model. Our findings identify Endocan and its downstream signaling axis as a potential target to subdue GBM recurrence and highlight the importance of vascular-tumor interactions for GBM development.
Collapse
Affiliation(s)
- Soniya Bastola
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Marat S Pavlyukov
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| | - Neel Sharma
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Yasmin Ghochani
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Mayu A Nakano
- Precision Medicine Institute, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sree Deepthi Muthukrishnan
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Sang Yul Yu
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Min Soo Kim
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alireza Sohrabi
- Department of Bioengineering, University of Texas at Austin, Austin, TX, USA
| | - Natalia P Biscola
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daisuke Yamashita
- Department of Neurosurgery, Ehime University Graduate School of Medicine, Shitsukawa 454, Toon, Ehime, Japan
| | - Ksenia S Anufrieva
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine of Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow, Russia
| | | | - Grace Jung
- Department of Medicine, Center for Iron Disorders, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Tomas Ganz
- Department of Medicine, Center for Iron Disorders, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Beatrice O'Brien
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Riki Kawaguchi
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Interdepartmental Program in Bioinformatics, Program in Neurogenetics, Department of Neurology and Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Yue Qin
- Interdepartmental Program in Bioinformatics, Program in Neurogenetics, Department of Neurology and Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | | | - Alma L Burlingame
- Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
| | - Juan A Oses-Prieto
- Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA
| | - Leif A Havton
- Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, James J Peters VA Medical Center, Bronx, NY, USA
| | - Steven A Goldman
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anita B Hjelmeland
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ichiro Nakano
- Department of Neurosurgery, Harada Hospital, Iruma, Saitama, Japan.
| | - Harley I Kornblum
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
| |
Collapse
|
6
|
Škarková A, Pelantová M, Tolde O, Legátová A, Mateu R, Bušek P, Garcia‐Borja E, Šedo A, Etienne‐Manneville S, Rösel D, Brábek J. Microtubule-associated NAV3 regulates invasive phenotypes in glioblastoma cells. Brain Pathol 2025; 35:e13294. [PMID: 39097525 PMCID: PMC11669409 DOI: 10.1111/bpa.13294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 07/17/2024] [Indexed: 08/05/2024] Open
Abstract
Glioblastomas are aggressive brain tumors for which effective therapy is still lacking, resulting in dismal survival rates. These tumors display significant phenotypic plasticity, harboring diverse cell populations ranging from tumor core cells to dispersed, highly invasive cells. Neuron navigator 3 (NAV3), a microtubule-associated protein affecting microtubule growth and dynamics, is downregulated in various cancers, including glioblastoma, and has thus been considered a tumor suppressor. In this study, we challenge this designation and unveil distinct expression patterns of NAV3 across different invasion phenotypes. Using glioblastoma cell lines and patient-derived glioma stem-like cell cultures, we disclose an upregulation of NAV3 in invading glioblastoma cells, contrasting with its lower expression in cells residing in tumor spheroid cores. Furthermore, we establish an association between low and high NAV3 expression and the amoeboid and mesenchymal invasive phenotype, respectively, and demonstrate that overexpression of NAV3 directly stimulates glioblastoma invasive behavior in both 2D and 3D environments. Consistently, we observed increased NAV3 expression in cells migrating along blood vessels in mouse xenografts. Overall, our results shed light on the role of NAV3 in glioblastoma invasion, providing insights into this lethal aspect of glioblastoma behavior.
Collapse
Affiliation(s)
- Aneta Škarková
- Laboratory of Cancer Cell Invasion, Department of Cell Biology, BIOCEV, Faculty of ScienceCharles UniversityVestecCzech Republic
| | - Markéta Pelantová
- Laboratory of Cancer Cell Invasion, Department of Cell Biology, BIOCEV, Faculty of ScienceCharles UniversityVestecCzech Republic
| | - Ondřej Tolde
- Laboratory of Cancer Cell Invasion, Department of Cell Biology, BIOCEV, Faculty of ScienceCharles UniversityVestecCzech Republic
| | - Anna Legátová
- Laboratory of Cancer Cell Invasion, Department of Cell Biology, BIOCEV, Faculty of ScienceCharles UniversityVestecCzech Republic
| | - Rosana Mateu
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of MedicineCharles UniversityPragueCzech Republic
| | - Petr Bušek
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of MedicineCharles UniversityPragueCzech Republic
| | - Elena Garcia‐Borja
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of MedicineCharles UniversityPragueCzech Republic
| | - Aleksi Šedo
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of MedicineCharles UniversityPragueCzech Republic
| | | | - Daniel Rösel
- Laboratory of Cancer Cell Invasion, Department of Cell Biology, BIOCEV, Faculty of ScienceCharles UniversityVestecCzech Republic
| | - Jan Brábek
- Laboratory of Cancer Cell Invasion, Department of Cell Biology, BIOCEV, Faculty of ScienceCharles UniversityVestecCzech Republic
| |
Collapse
|
7
|
Novak M, Majc B, Malavolta M, Porčnik A, Mlakar J, Hren M, Habič A, Mlinar M, Jovčevska I, Šamec N, Zottel A, Skoblar Vidmar M, Vipotnik Vesnaver T, Zupan A, Matjašič A, Trkov Bobnar S, Georgiev D, Sadikov A, Bošnjak R, Prestor B, Komel R, Lah Turnšek T, Breznik B. The Slovenian translational platform GlioBank for brain tumor research: Identification of molecular signatures of glioblastoma progression. Neurooncol Adv 2025; 7:vdaf015. [PMID: 39963438 PMCID: PMC11831694 DOI: 10.1093/noajnl/vdaf015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2025] Open
Abstract
Background Glioblastoma (GB) is one of the most lethal solid tumors in humans, with an average patient life expectancy of 15 months and a 5-year survival rate of 5%-10%. GB is still uncurable due to tumor heterogeneity and invasive nature as well as therapy-resistant cancer cells. Centralized biobanks with clinical data and corresponding biological material of GB patients facilitate the development of new treatment approaches and the search for clinically relevant biomarkers, with the goal of improving outcomes for GB patients. The aim of this study was firstly to establish a Slovenian translation platform, GlioBank, and secondly to demonstrate its utility through the identification of molecular signatures associated with GB progression and patient survival. Methods GlioBank contains tissue samples and corresponding tumor models as well as clinical data from patients diagnosed with glioma, with a focus on GB. Primary GB cells, glioblastoma stem cells (GSCs), and organoids have been established from fresh tumor biopsies. We performed expression analyses of genes associated with GB progression and bioinformatics analyses of available clinical and research data obtained from a subset of 91 GB patients. qPCR was performed to determine the expression of genes associated with therapy resistance and cancer cell invasion, including markers of different GB subtypes, GSCs, epithelial-to-mesenchymal transition, and immunomodulation/chemokine signaling in tumor tissues and corresponding cellular models. Results GlioBank contains biological material and research, and clinical data collected in the SciNote electronic laboratory notebook. To date, more than 240 glioma tissue samples have been collected and stored in GlioBank, most of which are GB tissues (205) and were further processed to establish primary GB cells (n = 64), GSCs (n = 14), and GB organoids (n = 17). Corresponding blood plasma (n = 103) and peripheral blood mononuclear cells (n = 101) are also stored. GB tumors were classified into 4 different subtypes that differed regarding patient survival; the mixed subtype exhibited the longest patient survival. High DAB2, S100A4, and STAT3 expression were associated with poor overall patient survival, and DAB2 was found to be an independent prognostic marker for GB survival. We analyzed the molecular signatures between different tumor regions (core vs. rim). STMN4, ERBB3, and ACSBG1 were upregulated in the tumor rim, suggesting that these genes are associated with the invasive nature of GB. Conclusions GlioBank is a centralized biobank that has been built by a multidisciplinary network with the aim of facilitating disease-oriented basic and clinical research. The advantages of GlioBank include the molecular characterization of GB based on targeted gene expression, the availability of diverse cellular models (eg, GB cells and organoids), and a large number of patient-matched tumor core and rim samples, all with accompanying molecular and clinical data. We report here for the first time an association between DAB2 expression and low overall survival in GB patients, indicative of a prognostic value of DAB2.
Collapse
Affiliation(s)
- Metka Novak
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Bernarda Majc
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Marta Malavolta
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Andrej Porčnik
- Department of Neurosurgery, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Jernej Mlakar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | | | - Anamarija Habič
- Jožef Stefan International Postgraduate School, Ljubljana, Slovenia
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Mateja Mlinar
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Ivana Jovčevska
- Medical Centre for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Neja Šamec
- Medical Centre for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Alja Zottel
- Medical Centre for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | | | | | - Andrej Zupan
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Alenka Matjašič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | | | - Dejan Georgiev
- Faculty of Computer and Information Science, University of Ljubljana, Ljubljana, Slovenia
| | - Aleksander Sadikov
- Faculty of Computer and Information Science, University of Ljubljana, Ljubljana, Slovenia
| | - Roman Bošnjak
- Department of Neurosurgery, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Borut Prestor
- Department of Neurosurgery, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Radovan Komel
- Medical Centre for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tamara Lah Turnšek
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Barbara Breznik
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| |
Collapse
|
8
|
Jackson LR, Erickson A, Camphausen K, Krauze AV. Understanding the Immune System and Biospecimen-Based Response in Glioblastoma: A Practical Guide to Utilizing Signal Redundancy for Biomarker and Immune Signature Discovery. Curr Oncol 2024; 32:16. [PMID: 39851932 PMCID: PMC11763554 DOI: 10.3390/curroncol32010016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/12/2024] [Accepted: 12/22/2024] [Indexed: 01/26/2025] Open
Abstract
Glioblastoma (GBM) is a primary central nervous system malignancy with a median survival of 15-20 months. The presence of both intra- and intertumoral heterogeneity limits understanding of biological mechanisms leading to tumor resistance, including immune escape. An attractive field of research to examine treatment resistance are immune signatures composed of cluster of differentiation (CD) markers and cytokines. CD markers are surface markers expressed on various cells throughout the body, often associated with immune cells. Cytokines are the effector molecules of the immune system. Together, CD markers and cytokines can serve as useful biomarkers to reflect immune status in patients with GBM. However, there are gaps in the understanding of the intricate interactions between GBM and the peripheral immune system and how these interactions change with standard and immune-modulating treatments. The key to understanding the true nature of these interactions is through multi-omic analysis of tumor progression and treatment response. This review aims to identify potential non-invasive blood-based biomarkers that can contribute to an immune signature through multi-omic approaches, leading to a better understanding of immune involvement in GBM.
Collapse
Affiliation(s)
| | | | | | - Andra V. Krauze
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health, 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA; (L.R.J.); (A.E.); (K.C.)
| |
Collapse
|
9
|
Skouras P, Markouli M, Papadatou I, Piperi C. Targeting epigenetic mechanisms of resistance to chemotherapy in gliomas. Crit Rev Oncol Hematol 2024; 204:104532. [PMID: 39406277 DOI: 10.1016/j.critrevonc.2024.104532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024] Open
Abstract
Glioma, an aggressive type of brain tumors of glial origin is highly heterogeneous, posing significant treatment challenges due to its intrinsic resistance to conventional therapeutic schemes. It is characterized by an interplay between epigenetic and genetic alterations in key signaling pathways which further endorse their resistance potential. Aberrant DNA methylation patterns, histone modifications and non-coding RNAs may alter the expression of genes associated with drug response and cell survival, induce gene silencing or deregulate key pathways contributing to glioma resistance. There is evidence that epigenetic plasticity enables glioma cells to adapt dynamically to therapeutic schemes and allow the formation of drug-resistant subpopulations. Furthermore, the tumor microenvironment adds an extra input on epigenetic regulation, increasing the complexity of resistance mechanisms. Herein, we discuss epigenetic changes conferring to drug resistance mechanisms in gliomas in order to delineate novel therapeutic targets and potential approaches that will enable personalized treatment.
Collapse
Affiliation(s)
- Panagiotis Skouras
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece; 1st Department of Neurosurgery, Evangelismos Hospital, National and Kapodistrian University of Athens, Greece.
| | - Mariam Markouli
- Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118, USA.
| | - Ioanna Papadatou
- University Research Institute for the Study of Genetic & Malignant Disorders in Childhood, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens, Athens 11527, Greece.
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece.
| |
Collapse
|
10
|
Zhao W, Wang J, Zhao F, Li Y, Li Z, Li X, Chen A. SUMOylation modification of HNRNPK at the K422 site promotes invasion in glioblastoma. Int J Biol Sci 2024; 20:5715-5730. [PMID: 39494331 PMCID: PMC11528450 DOI: 10.7150/ijbs.102051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 10/09/2024] [Indexed: 11/05/2024] Open
Abstract
Glioblastoma multiforme (GBM) is a highly heterogeneous brain tumor with limited treatment options. Recent studies revealed cellular heterogeneity and the potential for interconversion between distinct cell types on the basis of RNA sequencing and single-cell analyses. The ability of different cell types to adapt to their surrounding environment and undergo transformation significantly complicates the study and treatment of GBM. In this study, we reveal that HNRNPK-SUMO1 expression is predominantly found in the GBM infiltration area. SUMOylation of the K422 residue of HNRNPK interferes with its DNA binding ability, thereby disrupting downstream transcription, and ultimately leading to transitions between different states of glioblastoma stem cells. Although the proneural subtype is considered to have a better prognosis, transitioning towards this state promotes tumor invasion. These findings serve as a reminder to exercise caution when considering treatments targeting specific cellular subtypes.
Collapse
Affiliation(s)
- Wenguo Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Health and Function Remodeling, Jinan, 250017, China
| | - Jiazheng Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Health and Function Remodeling, Jinan, 250017, China
| | - Feihu Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Health and Function Remodeling, Jinan, 250017, China
| | - Yaquan Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Health and Function Remodeling, Jinan, 250017, China
| | - Zhuo Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Health and Function Remodeling, Jinan, 250017, China
| | - Xingang Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Health and Function Remodeling, Jinan, 250017, China
| | - Anjing Chen
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Health and Function Remodeling, Jinan, 250017, China
| |
Collapse
|
11
|
Manoharan VT, Abdelkareem A, Gill G, Brown S, Gillmor A, Hall C, Seo H, Narta K, Grewal S, Dang NH, Ahn BY, Osz K, Lun X, Mah L, Zemp F, Mahoney D, Senger DL, Chan JA, Morrissy AS. Spatiotemporal modeling reveals high-resolution invasion states in glioblastoma. Genome Biol 2024; 25:264. [PMID: 39390467 PMCID: PMC11465563 DOI: 10.1186/s13059-024-03407-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 09/29/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND Diffuse invasion of glioblastoma cells through normal brain tissue is a key contributor to tumor aggressiveness, resistance to conventional therapies, and dismal prognosis in patients. A deeper understanding of how components of the tumor microenvironment (TME) contribute to overall tumor organization and to programs of invasion may reveal opportunities for improved therapeutic strategies. RESULTS Towards this goal, we apply a novel computational workflow to a spatiotemporally profiled GBM xenograft cohort, leveraging the ability to distinguish human tumor from mouse TME to overcome previous limitations in the analysis of diffuse invasion. Our analytic approach, based on unsupervised deconvolution, performs reference-free discovery of cell types and cell activities within the complete GBM ecosystem. We present a comprehensive catalogue of 15 tumor cell programs set within the spatiotemporal context of 90 mouse brain and TME cell types, cell activities, and anatomic structures. Distinct tumor programs related to invasion align with routes of perivascular, white matter, and parenchymal invasion. Furthermore, sub-modules of genes serving as program network hubs are highly prognostic in GBM patients. CONCLUSION The compendium of programs presented here provides a basis for rational targeting of tumor and/or TME components. We anticipate that our approach will facilitate an ecosystem-level understanding of the immediate and long-term consequences of such perturbations, including the identification of compensatory programs that will inform improved combinatorial therapies.
Collapse
Affiliation(s)
- Varsha Thoppey Manoharan
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Aly Abdelkareem
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Gurveer Gill
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Samuel Brown
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Aaron Gillmor
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Courtney Hall
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Heewon Seo
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Kiran Narta
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Sean Grewal
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Ngoc Ha Dang
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Bo Young Ahn
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Kata Osz
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Xueqing Lun
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Laura Mah
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Franz Zemp
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Douglas Mahoney
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
| | - Donna L Senger
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
| | - Jennifer A Chan
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada.
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
| | - A Sorana Morrissy
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada.
- Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada.
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
| |
Collapse
|
12
|
Pelaz SG, Flores-Hernández R, Vujic T, Schvartz D, Álvarez-Vázquez A, Ding Y, García-Vicente L, Belloso A, Talaverón R, Sánchez JC, Tabernero A. A proteomic approach supports the clinical relevance of TAT-Cx43 266-283 in glioblastoma. Transl Res 2024; 272:95-110. [PMID: 38876188 DOI: 10.1016/j.trsl.2024.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/18/2024] [Accepted: 06/01/2024] [Indexed: 06/16/2024]
Abstract
Glioblastoma (GBM) is the most frequent and aggressive primary brain cancer. The Src inhibitor, TAT-Cx43266-283, exerts antitumor effects in in vitro and in vivo models of GBM. Because addressing the mechanism of action is essential to translate these results to a clinical setting, in this study we carried out an unbiased proteomic approach. Data-independent acquisition mass spectrometry proteomics allowed the identification of 190 proteins whose abundance was modified by TAT-Cx43266-283. Our results were consistent with the inhibition of Src as the mechanism of action of TAT-Cx43266-283 and unveiled antitumor effectors, such as p120 catenin. Changes in the abundance of several proteins suggested that TAT-Cx43266-283 may also impact the brain microenvironment. Importantly, the proteins whose abundance was reduced by TAT-Cx43266-283 correlated with an improved GBM patient survival in clinical datasets and none of the proteins whose abundance was increased by TAT-Cx43266-283 correlated with shorter survival, supporting its use in clinical trials.
Collapse
Affiliation(s)
- Sara G Pelaz
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain.
| | - Raquel Flores-Hernández
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | - Tatjana Vujic
- Department of Medicine, University of Geneva, 1211, Geneva, Switzerland; University Center of Legal Medicine, Lausanne-Geneva, Lausanne University Hospital and University of Lausanne, Geneva University Hospital and University of Geneva, Lausanne Geneva, Switzerland
| | - Domitille Schvartz
- Department of Medicine, University of Geneva, 1211, Geneva, Switzerland; University of Geneva, Faculty of Medicine, Proteomics Core Facility, Geneva, Switzerland
| | - Andrea Álvarez-Vázquez
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | - Yuxin Ding
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | - Laura García-Vicente
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | - Aitana Belloso
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | - Rocío Talaverón
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | | | - Arantxa Tabernero
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain.
| |
Collapse
|
13
|
Majc B, Habič A, Malavolta M, Vittori M, Porčnik A, Bošnjak R, Mlakar J, Matjašič A, Zupan A, Vidmar MS, Turnšek TL, Sadikov A, Breznik B, Novak M. Patient-derived tumor organoids mimic treatment-induced DNA damage response in glioblastoma. iScience 2024; 27:110604. [PMID: 39252971 PMCID: PMC11381849 DOI: 10.1016/j.isci.2024.110604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 03/11/2024] [Accepted: 07/25/2024] [Indexed: 09/11/2024] Open
Abstract
Glioblastoma (GB) is the most common primary malignant brain tumor, characterized by resistance to therapy. Despite aggressive treatment options, GB remains an incurable disease. Invasiveness and heterogeneity are key GB features that cannot be studied in preclinical in vitro models. In this study, we investigated the effects of standard therapy using patient-derived GB organoids (GBOs). GBOs reflect the complexity and heterogeneity of the original tumor tissue. No significant effect on GBO viability or invasion was observed after irradiation and temozolomide treatment. E3 ubiquitin-protein ligase (MDM2), cyclin-dependent kinase inhibitor 1A (CDKN1A), and the serine/threonine kinases ATM and ATR were upregulated at the gene and protein levels after treatment. Our results show that the p53 pathway and DNA-damage response mechanisms were triggered, suggesting that GBOs recapitulate GB therapy resistance. GBOs thus provide a highly efficient platform to assess the specific responses of GB patients to therapy and to further explore therapy resistance.
Collapse
Affiliation(s)
- Bernarda Majc
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia
- Jožef Stefan International Postgraduate School, Nanosciences and Nanotechnologies, 1000 Ljubljana, Slovenia
| | - Anamarija Habič
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia
- Jožef Stefan International Postgraduate School, Nanosciences and Nanotechnologies, 1000 Ljubljana, Slovenia
| | - Marta Malavolta
- University of Ljubljana, Faculty of Computer and Information Science, 1000 Ljubljana, Slovenia
| | - Miloš Vittori
- University of Ljubljana, Biotechnical Faculty, Department of Biology, 1000 Ljubljana, Slovenia
| | - Andrej Porčnik
- Department of Neurosurgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
| | - Roman Bošnjak
- Department of Neurosurgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
| | - Jernej Mlakar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Alenka Matjašič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Andrej Zupan
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Marija Skoblar Vidmar
- Institute of Oncology, University Medical Centre Ljubljana, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Tamara Lah Turnšek
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia
| | - Aleksander Sadikov
- University of Ljubljana, Faculty of Computer and Information Science, 1000 Ljubljana, Slovenia
| | - Barbara Breznik
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia
| | - Metka Novak
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia
| |
Collapse
|
14
|
Kundu P, Jain R, Kanuri NN, Arimappamagan A, Santosh V, Kondaiah P. DNA Methylation in Recurrent Glioblastomas: Increased TEM8 Expression Activates the Src/PI3K/AKT/GSK-3β/B-Catenin Pathway. Cancer Genomics Proteomics 2024; 21:485-501. [PMID: 39191501 PMCID: PMC11363927 DOI: 10.21873/cgp.20466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/20/2024] [Accepted: 06/10/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND/AIM Glioblastomas (GBM) are infiltrative malignant brain tumors which mostly recur within a year's time following surgical resection and chemo-radiation therapy. Studies on glioblastoma cells following radio-chemotherapy, have been demonstrated to induce trans-differentiation, cellular plasticity, activation of DNA damage response and stemness. As glioblastomas are heterogenous tumors that develop treatment resistance and plasticity, we investigated if there exist genome-wide DNA methylation changes in recurrent tumors. MATERIALS AND METHODS Utilizing genome-wide DNA methylation arrays, we compared the DNA methylation profile of 11 primary (first occurrence) tumors with 13 recurrent (relapsed) GBM, to delineate the contribution of epigenetic changes associated with therapy exposure, therapy resistance, and relapse of disease. RESULTS Our data revealed 1,224 hypermethylated- and 526 hypomethylated-probes in recurrent glioblastomas compared to primary disease. We found differential methylation of solute carrier and ion channel genes, interleukin receptor/ligand genes, tumor-suppressor genes and genes associated with metastasis. We functionally characterized one such hypomethylated-up-regulated gene, namely anthrax toxin receptor 1/tumor endothelial marker 8 (ANTXR1/TEM8), whose expression was validated to be significantly up-regulated in recurrent glioblastomas compared to primary tumors and confirmed by immunohistochemistry. Using overexpression and knockdown approaches, we showed that TEM8 induces proliferation, invasion, migration, and chemo-radioresistance in glioblastoma cells. Additionally, we demonstrated a novel mechanism of β-catenin stabilization and activation of the β-catenin transcriptional program due to TEM8 overexpression via a Src/PI3K/AKT/GSK3β/β-catenin pathway. CONCLUSION We report genome-wide DNA methylation changes in recurrent GBM and suggest involvement of the TEM8 gene in GBM recurrence and progression.
Collapse
Affiliation(s)
- Paramita Kundu
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
- Breast Cancer Now Toby Robins Research Centre, Department of Breast Research, The Institute of Cancer Research, London, U.K
| | - Ruchi Jain
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
- Al Jalila Genomics Centre, Al Jalila Children's Hospital, Dubai, United Arab Emirates
| | - Nandaki Nag Kanuri
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | | | - Vani Santosh
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Paturu Kondaiah
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India;
| |
Collapse
|
15
|
Mousavikia SN, Darvish L, Bahreyni Toossi MT, Azimian H. Exosomes: Their role in the diagnosis, progression, metastasis, and treatment of glioblastoma. Life Sci 2024; 350:122743. [PMID: 38806071 DOI: 10.1016/j.lfs.2024.122743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 05/10/2024] [Accepted: 05/22/2024] [Indexed: 05/30/2024]
Abstract
Exosomes are crucial for the growth and spread of glioblastomas, an aggressive form of brain cancer. These tiny vesicles play a crucial role in the activation of signaling pathways and intercellular communication. They can also transfer a variety of biomolecules such as proteins, lipids and nucleic acids from donor to recipient cells. Exosomes can influence the immune response by regulating the activity of immune cells, and they are crucial for the growth and metastasis of glioblastoma cells. In addition, exosomes contribute to drug resistance during treatment, which is a major obstacle in the treatment of glioblastoma. By studying them, the diagnosis and prognosis of glioblastoma can be improved. Due to their high biocompatibility and lack of toxicity, they have become an attractive option for drug delivery. The development of exosomes as carriers of specific therapeutic agents could overcome some of the obstacles to effective treatment of glioblastoma. In this review, we address the potential of exosomes for the treatment of glioblastoma and show how they can be modified for this purpose.
Collapse
Affiliation(s)
- S N Mousavikia
- Medical Physics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - L Darvish
- Department of Radiology, Faculty of Paramedicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran; Mother and Child Welfare Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - M T Bahreyni Toossi
- Medical Physics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - H Azimian
- Medical Physics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
16
|
Jensen KT, Nielsen NS, Viana Almeida A, Thøgersen IB, Enghild JJ, Harwood SL. Proteolytic cleavage of the TGFβ co-receptor CD109 changes its conformation, resulting in protease inhibition via activation of its thiol ester, and dissociation from the cell membrane. FEBS J 2024; 291:3169-3190. [PMID: 38587194 DOI: 10.1111/febs.17128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 02/14/2024] [Accepted: 03/18/2024] [Indexed: 04/09/2024]
Abstract
The glycosylphosphatidylinositol (GPI)-anchored protein cluster of differentiation 109 (CD109) is expressed on many human cell types and modulates the transforming growth factor β (TGF-β) signaling network. CD109 belongs to the alpha-macroglobulin family of proteins, known for their protease-triggered conformational changes. However, the effect of proteolysis on CD109 and its conformation are unknown. Here, we investigated the interactions of CD109 with proteases. We found that a diverse selection of proteases cleaved peptide bonds within the predicted bait region of CD109, inducing a conformational change that activated the thiol ester of CD109. We show CD109 was able to conjugate proteases with this thiol ester and decrease their activity toward protein substrates, demonstrating that CD109 is a protease inhibitor. We additionally found that CD109 has a unique mechanism whereby its GPI-anchored macroglobulin 8 (MG8) domain dissociates during its conformational change, allowing proteases to release CD109 from the cell surface by a precise mechanism and not unspecific shedding. We conclude that proteolysis of the CD109 bait region affects both its structure and location, and that interactions between CD109 and proteases may be important to understanding its functions, for example, as a TGF-β co-receptor.
Collapse
Affiliation(s)
| | | | - Ana Viana Almeida
- Department of Molecular Biology and Genetics, Aarhus University, Denmark
| | - Ida B Thøgersen
- Department of Molecular Biology and Genetics, Aarhus University, Denmark
| | - Jan J Enghild
- Department of Molecular Biology and Genetics, Aarhus University, Denmark
| | | |
Collapse
|
17
|
Ocaña-Tienda B, Pérez-García VM. Mathematical modeling of brain metastases growth and response to therapies: A review. Math Biosci 2024; 373:109207. [PMID: 38759950 DOI: 10.1016/j.mbs.2024.109207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 04/04/2024] [Accepted: 05/10/2024] [Indexed: 05/19/2024]
Abstract
Brain metastases (BMs) are the most common intracranial tumor type and a significant health concern, affecting approximately 10% to 30% of all oncological patients. Although significant progress is being made, many aspects of the metastatic process to the brain and the growth of the resulting lesions are still not well understood. There is a need for an improved understanding of the growth dynamics and the response to treatment of these tumors. Mathematical models have been proven valuable for drawing inferences and making predictions in different fields of cancer research, but few mathematical works have considered BMs. This comprehensive review aims to establish a unified platform and contribute to fostering emerging efforts dedicated to enhancing our mathematical understanding of this intricate and challenging disease. We focus on the progress made in the initial stages of mathematical modeling research regarding BMs and the significant insights gained from such studies. We also explore the vital role of mathematical modeling in predicting treatment outcomes and enhancing the quality of clinical decision-making for patients facing BMs.
Collapse
Affiliation(s)
- Beatriz Ocaña-Tienda
- Mathematical Oncology Laboratory (MOLAB), University of Castilla-La Mancha, Avda. Camilo José Cela s/n, 13071, Ciudad Real, Spain.
| | - Víctor M Pérez-García
- Mathematical Oncology Laboratory (MOLAB), University of Castilla-La Mancha, Avda. Camilo José Cela s/n, 13071, Ciudad Real, Spain.
| |
Collapse
|
18
|
Jiang X, You H, Niu Y, Ding Y, Chen Z, Wang H, Xu Y, Zhou P, Wei L, Deng D, Xue L, Peng Y, Yang Y, Fan L, Shao N. E2F1-regulated USP5 contributes to the tumorigenic capacity of glioma stem cells through the maintenance of OCT4 stability. Cancer Lett 2024; 593:216875. [PMID: 38643837 DOI: 10.1016/j.canlet.2024.216875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 03/27/2024] [Accepted: 04/07/2024] [Indexed: 04/23/2024]
Abstract
Mesenchymal glioma stem cells (MES GSCs) are a subpopulation of cells in glioblastoma (GBM) that contribute to a worse prognosis owing to their highly aggressive nature and resistance to radiation therapy. Here, OCT4 is characterized as a critical factor in sustaining the stemness phenotype of MES GSC. We find that OCT4 is expressed intensively in MES GSC and is intimately associated with poor prognosis, moreover, OCT4 depletion leads to diminished invasive capacity and impairment of the stem phenotype in MES GSC. Subsequently, we demonstrated that USP5 is a deubiquitinating enzyme which directly interacts with OCT4 and preserves OCT4 stability through its deubiquitination. USP5 was additionally proven to be aberrantly over-expressed in MES GSCs, and its depletion resulted in a noticeable diminution of OCT4 and consequently a reduced self-renewal and tumorigenic capacity of MES GSCs, which can be substantially restored by ectopic expression of OCT4. In addition, we detected the dominant molecule that regulates USP5 transcription, E2F1, with dual luciferase reporter gene analysis. In combination, targeting the E2F1-USP5-OCT4 axis is a potentially emerging strategy for the therapy of GBM.
Collapse
Affiliation(s)
- Xiao Jiang
- Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
| | - Hongtao You
- Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
| | - Yixuan Niu
- Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
| | - Yudan Ding
- Translational Medicine Research Center, Zhujiang Hospital of Southern Medical University, 510280, Guangdong Province, China.
| | - Zhengxin Chen
- Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.
| | - Huibo Wang
- Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.
| | - Yuan Xu
- Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China; Clinical Medical Research Center, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
| | - Peng Zhou
- Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
| | - Li Wei
- Department of Blood Transfusion, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
| | - Danni Deng
- Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China; Clinical Medical Research Center, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
| | - Lian Xue
- Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China; Clinical Medical Research Center, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
| | - Ya Peng
- Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China; Clinical Medical Research Center, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
| | - Yilin Yang
- Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
| | - Ligang Fan
- Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
| | - Naiyuan Shao
- Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
| |
Collapse
|
19
|
Hosen S, Ikeda-Yorifuji I, Yamashita T. Asporin and CD109, expressed in the injured neonatal spinal cord, attenuate axonal re-growth in vitro. Neurosci Lett 2024; 833:137832. [PMID: 38796094 DOI: 10.1016/j.neulet.2024.137832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 05/17/2024] [Accepted: 05/22/2024] [Indexed: 05/28/2024]
Abstract
Axonal regeneration is restricted in adults and causes irreversible motor dysfunction following spinal cord injury (SCI). In contrast, neonates have prominent regenerative potential and can restore their neural function. Although the distinct cellular responses in neonates have been studied, how they contribute to neural recovery remains unclear. To assess whether the secreted molecules in neonatal SCI can enhance neural regeneration, we re-analyzed the previously performed single-nucleus RNA-seq (snRNA-seq) and focused on Asporin and Cd109, the highly expressed genes in the injured neonatal spinal cord. In the present study, we showed that both these molecules were expressed in the injured spinal cords of adults and neonates. We treated the cortical neurons with recombinant Asporin or CD109 to observe their direct effects on neurons in vitro. We demonstrated that these molecules enhance neurite outgrowth in neurons. However, these molecules did not enhance re-growth of severed axons. Our results suggest that Asporin and CD109 influence neurites at the lesion site, rather than promoting axon regeneration, to restore neural function in neonates after SCI.
Collapse
Affiliation(s)
- Sakura Hosen
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Iyo Ikeda-Yorifuji
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan.
| | - Toshihide Yamashita
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan; WPI Immunology Frontier Research Center, Osaka University, Suita, Japan; Department of Molecular Neuroscience, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan; Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, Suita, Japan.
| |
Collapse
|
20
|
Park JH, Hothi P, de Lomana ALG, Pan M, Calder R, Turkarslan S, Wu WJ, Lee H, Patel AP, Cobbs C, Huang S, Baliga NS. Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells. SCIENCE ADVANCES 2024; 10:eadj7706. [PMID: 38848360 PMCID: PMC11160475 DOI: 10.1126/sciadv.adj7706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 05/03/2024] [Indexed: 06/09/2024]
Abstract
Poor prognosis and drug resistance in glioblastoma (GBM) can result from cellular heterogeneity and treatment-induced shifts in phenotypic states of tumor cells, including dedifferentiation into glioma stem-like cells (GSCs). This rare tumorigenic cell subpopulation resists temozolomide, undergoes proneural-to-mesenchymal transition (PMT) to evade therapy, and drives recurrence. Through inference of transcriptional regulatory networks (TRNs) of patient-derived GSCs (PD-GSCs) at single-cell resolution, we demonstrate how the topology of transcription factor interaction networks drives distinct trajectories of cell-state transitions in PD-GSCs resistant or susceptible to cytotoxic drug treatment. By experimentally testing predictions based on TRN simulations, we show that drug treatment drives surviving PD-GSCs along a trajectory of intermediate states, exposing vulnerability to potentiated killing by siRNA or a second drug targeting treatment-induced transcriptional programs governing nongenetic cell plasticity. Our findings demonstrate an approach to uncover TRN topology and use it to rationally predict combinatorial treatments that disrupt acquired resistance in GBM.
Collapse
Affiliation(s)
| | - Parvinder Hothi
- Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, USA
| | | | - Min Pan
- Institute for Systems Biology, Seattle, WA, USA
| | | | | | - Wei-Ju Wu
- Institute for Systems Biology, Seattle, WA, USA
| | - Hwahyung Lee
- Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, USA
| | - Anoop P. Patel
- Department of Neurosurgery, Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA
- Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA
| | - Charles Cobbs
- Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, USA
| | - Sui Huang
- Institute for Systems Biology, Seattle, WA, USA
| | - Nitin S. Baliga
- Institute for Systems Biology, Seattle, WA, USA
- Departments of Microbiology, Biology, and Molecular Engineering Sciences, University of Washington, Seattle, WA, USA
| |
Collapse
|
21
|
Hart WS, Myers PJ, Purow BW, Lazzara MJ. Divergent transcriptomic signatures from putative mesenchymal stimuli in glioblastoma cells. Cancer Gene Ther 2024; 31:851-860. [PMID: 38337036 PMCID: PMC11192628 DOI: 10.1038/s41417-023-00724-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 02/12/2024]
Abstract
In glioblastoma, a mesenchymal phenotype is associated with especially poor patient outcomes. Various glioblastoma microenvironmental factors and therapeutic interventions are purported drivers of the mesenchymal transition, but the degree to which these cues promote the same mesenchymal transitions and the uniformity of those transitions, as defined by molecular subtyping systems, is unknown. Here, we investigate this question by analyzing publicly available patient data, surveying commonly measured transcripts for mesenchymal transitions in glioma-initiating cells (GIC), and performing next-generation RNA sequencing of GICs. Analysis of patient tumor data reveals that TGFβ, TNFα, and hypoxia signaling correlate with the mesenchymal subtype more than the proneural subtype. In cultured GICs, the microenvironment-relevant growth factors TGFβ and TNFα and the chemotherapeutic temozolomide promote expression of commonly measured mesenchymal transcripts. However, next-generation RNA sequencing reveals that growth factors and temozolomide broadly promote expression of both mesenchymal and proneural transcripts, in some cases with equal frequency. These results suggest that glioblastoma mesenchymal transitions do not occur as distinctly as in epithelial-derived cancers, at least as determined using common subtyping ontologies and measuring response to growth factors or chemotherapeutics. Further understanding of these issues may identify improved methods for pharmacologically targeting the mesenchymal phenotype in glioblastoma.
Collapse
Affiliation(s)
- William S Hart
- Department of Chemical Engineering, University of Virginia, Charlottesville, VA, 22903, USA
| | - Paul J Myers
- Department of Chemical Engineering, University of Virginia, Charlottesville, VA, 22903, USA
| | - Benjamin W Purow
- Department of Neurology, University of Virginia, Charlottesville, VA, 22903, USA
| | - Matthew J Lazzara
- Department of Chemical Engineering, University of Virginia, Charlottesville, VA, 22903, USA.
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22903, USA.
| |
Collapse
|
22
|
Wu Q, Berglund AE, Macaulay RJ, Etame AB. The Role of Mesenchymal Reprogramming in Malignant Clonal Evolution and Intra-Tumoral Heterogeneity in Glioblastoma. Cells 2024; 13:942. [PMID: 38891074 PMCID: PMC11171993 DOI: 10.3390/cells13110942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/26/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
Glioblastoma (GBM) is the most common yet uniformly fatal adult brain cancer. Intra-tumoral molecular and cellular heterogeneities are major contributory factors to therapeutic refractoriness and futility in GBM. Molecular heterogeneity is represented through molecular subtype clusters whereby the proneural (PN) subtype is associated with significantly increased long-term survival compared to the highly resistant mesenchymal (MES) subtype. Furthermore, it is universally recognized that a small subset of GBM cells known as GBM stem cells (GSCs) serve as reservoirs for tumor recurrence and progression. The clonal evolution of GSC molecular subtypes in response to therapy drives intra-tumoral heterogeneity and remains a critical determinant of GBM outcomes. In particular, the intra-tumoral MES reprogramming of GSCs using current GBM therapies has emerged as a leading hypothesis for therapeutic refractoriness. Preventing the intra-tumoral divergent evolution of GBM toward the MES subtype via new treatments would dramatically improve long-term survival for GBM patients and have a significant impact on GBM outcomes. In this review, we examine the challenges of the role of MES reprogramming in the malignant clonal evolution of glioblastoma and provide future perspectives for addressing the unmet therapeutic need to overcome resistance in GBM.
Collapse
Affiliation(s)
- Qiong Wu
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Anders E. Berglund
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Robert J. Macaulay
- Departments of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
| | - Arnold B. Etame
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
| |
Collapse
|
23
|
Agosti E, Zeppieri M, Ghidoni M, Ius T, Tel A, Fontanella MM, Panciani PP. Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments. World J Stem Cells 2024; 16:604-614. [PMID: 38817336 PMCID: PMC11135247 DOI: 10.4252/wjsc.v16.i5.604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 03/06/2024] [Accepted: 04/19/2024] [Indexed: 05/24/2024] Open
Abstract
BACKGROUND Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy. Glioma stem cells (GSCs), a subset within tumors, contribute to resistance, tumor heterogeneity, and plasticity. Recent studies reveal GSCs' role in therapeutic resistance, driven by DNA repair mechanisms and dynamic transitions between cellular states. Resistance mechanisms can involve different cellular pathways, most of which have been recently reported in the literature. Despite progress, targeted therapeutic approaches lack consensus due to GSCs' high plasticity. AIM To analyze targeted therapies against GSC-mediated resistance to radio- and chemotherapy in gliomas, focusing on underlying mechanisms. METHODS A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to September 30, 2023. The search strategy utilized relevant Medical Subject Heading terms and keywords related to including "glioma stem cells", "radiotherapy", "chemotherapy", "resistance", and "targeted therapies". Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated resistance to radiotherapy resistance (RTR). RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI, 452 papers were initially identified, with 203 chosen for full-text analysis. Among them, 201 were deemed eligible after excluding 168 for various reasons. The temporal breakdown of studies illustrates this trend: 2005-2010 (33.3%), 2011-2015 (36.4%), and 2016-2022 (30.3%). Key GSC models, particularly U87 (33.3%), U251 (15.2%), and T98G (15.2%), emerge as significant in research, reflecting their representativeness of glioma characteristics. Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) (27.3%) and Notch (12.1%) pathways, suggesting their crucial roles in resistance development. Targeted molecules with mTOR (18.2%), CHK1/2 (15.2%), and ATP binding cassette G2 (12.1%) as frequent targets underscore their importance in overcoming GSC-mediated resistance. Various therapeutic agents, notably RNA inhibitor/short hairpin RNA (27.3%), inhibitors (e.g., LY294002, NVP-BEZ235) (24.2%), and monoclonal antibodies (e.g., cetuximab) (9.1%), demonstrate versatility in targeted therapies. among 20 studies (60.6%), the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance (51.5%), followed by reductions in carmustine resistance (9.1%) and doxorubicin resistance (3.0%), while resistance to RTR is reduced in 42.4% of studies. CONCLUSION GSCs play a complex role in mediating radioresistance and chemoresistance, emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population and the dynamic tumor microenvironment to enhance outcomes for glioblastoma patients.
Collapse
Affiliation(s)
- Edoardo Agosti
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy.
| | - Mattia Ghidoni
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Tamara Ius
- Neurosurgery Unit, Department of Head-Neck and NeuroScience, University Hospital of Udine, Udine 33100, Italy
| | - Alessandro Tel
- Clinic of Maxillofacial Surgery, Department of Head-Neck and NeuroScience, University Hospital of Udine, Udine 33100, Italy
| | - Marco Maria Fontanella
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Pier Paolo Panciani
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| |
Collapse
|
24
|
Thompson E, Prior S, Brüning-Richardson A. Traditional Plant-Derived Compounds Inhibit Cell Migration and Induce Novel Cytoskeletal Effects in Glioblastoma Cells. J Xenobiot 2024; 14:613-633. [PMID: 38804289 PMCID: PMC11130960 DOI: 10.3390/jox14020036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/02/2024] [Accepted: 05/04/2024] [Indexed: 05/29/2024] Open
Abstract
Glioblastomas (GBMs) are aggressive and invasive cancers of the brain, associated with high rates of tumour recurrence and poor patient outcomes despite initial treatment. Targeting cell migration is therefore of interest in highly invasive cancers such as GBMs, to prevent tumour dissemination and regrowth. One current aim of GBM research focuses on assessing the anti-migratory properties of novel or repurposed inhibitors, including plant-based drugs which display anti-cancer properties. We investigated the potential anti-migratory activity of plant-based products with known cytotoxic effects in cancers, using a range of two-dimensional (2D) and three-dimensional (3D) migration and invasion assays as well as immunofluorescence microscopy to determine the specific anti-migratory and phenotypic effects of three plant-derived compounds, Turmeric, Indigo and Magnolia bark, on established glioma cell lines. Migrastatic activity was observed in all three drugs, with Turmeric exerting the most inhibitory effect on GBM cell migration into scratches and from the spheroid edge at all the timepoints investigated (p < 0.001). We also observed novel cytoskeletal phenotypes affecting actin and the focal adhesion dynamics. As our in vitro results determined that Turmeric, Indigo and Magnolia are promising migrastatic drugs, we suggest additional experimentation at the whole organism level to further validate these novel findings.
Collapse
Affiliation(s)
| | - Sally Prior
- Correspondence: (S.P.); (A.B.-R.); Tel.: +44-01484-472518 (A.B.-R.)
| | | |
Collapse
|
25
|
Xu C, Hou P, Li X, Xiao M, Zhang Z, Li Z, Xu J, Liu G, Tan Y, Fang C. Comprehensive understanding of glioblastoma molecular phenotypes: classification, characteristics, and transition. Cancer Biol Med 2024; 21:j.issn.2095-3941.2023.0510. [PMID: 38712813 PMCID: PMC11131044 DOI: 10.20892/j.issn.2095-3941.2023.0510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 03/28/2024] [Indexed: 05/08/2024] Open
Abstract
Among central nervous system-associated malignancies, glioblastoma (GBM) is the most common and has the highest mortality rate. The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently lead to tumor recurrence and sudden relapse in patients treated with temozolomide. In precision medicine, research on GBM treatment is increasingly focusing on molecular subtyping to precisely characterize the cellular and molecular heterogeneity, as well as the refractory nature of GBM toward therapy. Deep understanding of the different molecular expression patterns of GBM subtypes is critical. Researchers have recently proposed tetra fractional or tripartite methods for detecting GBM molecular subtypes. The various molecular subtypes of GBM show significant differences in gene expression patterns and biological behaviors. These subtypes also exhibit high plasticity in their regulatory pathways, oncogene expression, tumor microenvironment alterations, and differential responses to standard therapy. Herein, we summarize the current molecular typing scheme of GBM and the major molecular/genetic characteristics of each subtype. Furthermore, we review the mesenchymal transition mechanisms of GBM under various regulators.
Collapse
Affiliation(s)
- Can Xu
- School of Clinical Medicine, Hebei University, Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding 07100, China
- Hebei Key Laboratory of Precise Diagnosis and Treatment of Glioma, Baoding 071000, China
| | - Pengyu Hou
- Hebei Key Laboratory of Precise Diagnosis and Treatment of Glioma, Baoding 071000, China
- School of Basic Medical Sciences, Hebei University, Baoding 07100, China
| | - Xiang Li
- School of Basic Medical Sciences, Hebei University, Baoding 07100, China
| | - Menglin Xiao
- School of Clinical Medicine, Hebei University, Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding 07100, China
- Hebei Key Laboratory of Precise Diagnosis and Treatment of Glioma, Baoding 071000, China
| | - Ziqi Zhang
- School of Clinical Medicine, Hebei University, Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding 07100, China
- Hebei Key Laboratory of Precise Diagnosis and Treatment of Glioma, Baoding 071000, China
| | - Ziru Li
- Hebei Key Laboratory of Precise Diagnosis and Treatment of Glioma, Baoding 071000, China
- School of Basic Medical Sciences, Hebei University, Baoding 07100, China
| | - Jianglong Xu
- School of Clinical Medicine, Hebei University, Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding 07100, China
- Hebei Key Laboratory of Precise Diagnosis and Treatment of Glioma, Baoding 071000, China
| | - Guoming Liu
- School of Clinical Medicine, Hebei University, Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding 07100, China
- Hebei Key Laboratory of Precise Diagnosis and Treatment of Glioma, Baoding 071000, China
| | - Yanli Tan
- Hebei Key Laboratory of Precise Diagnosis and Treatment of Glioma, Baoding 071000, China
- School of Basic Medical Sciences, Hebei University, Baoding 07100, China
- Department of Pathology, Affiliated Hospital of Hebei University, Baoding 07100, China
| | - Chuan Fang
- School of Clinical Medicine, Hebei University, Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding 07100, China
- Hebei Key Laboratory of Precise Diagnosis and Treatment of Glioma, Baoding 071000, China
| |
Collapse
|
26
|
Lückstädt W, Rathod M, Möbus L, Bub S, Lucius R, Elsner F, Spindler V, Arnold P. CD109 drives pro-tumorigenic cell properties in human non-small cell lung cancer through interaction with desmoglein-2. RESEARCH SQUARE 2024:rs.3.rs-4102385. [PMID: 38562713 PMCID: PMC10984026 DOI: 10.21203/rs.3.rs-4102385/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Cluster of differentiation 109 (CD109) is a glycosylphosphatidylinositol (GPI) anchored cell surface protein, expressed on epithelial and endothelial cells, CD4+ and CD8+ T-cells, and premature lymphocytes. CD109 interacts with different cell surface receptors and thereby modulates intracellular signaling pathways, which ultimately changes cellular functions. One well-studied example is the interaction of CD109 with the TGFβ/TGFβ-receptor complex at the cell surface. CD109 silences intracellular SMAD2/3 signaling and targets TGFβ/TGFβ-receptor to the endosomal/lysosomal compartment. In recent years, CD109 emerged as a tumor marker for different tumor entities and expression of CD109 could be linked to adverse outcome in patients. In this study, we show that silencing of CD109 in human non-small cell lung cancer (NSCLC) cells, returns these cells to an epithelial like growth phenotype. On the transcriptional level, we describe changes in cell-cell contact and epithelial-mesenchymal transition associated gene clusters. At the cell surface, we identify desmoglein-2 (DSG2) as a new interaction partner of CD109 and demonstrate CD109 dependent targeting of DSG2 to the apical cell surface, where it forms desmosomes between apical and basal cell poles. Both, CD109 and DSG2 are genetic risk factors, linked to reduced overall survival in lung adenocarcinoma patients (subtype of NSCLC). In this study, we show the expression of both proteins in the same tumor and suggest a new CD109-DSG2 axis in NSCLC patients that could present a targetable therapeutic option in the future.
Collapse
Affiliation(s)
| | - Maitreyi Rathod
- Department of Biomedicine, University of Basel, Switzerland
- Institute of Anatomy and Experimental Morphology, University Clinic Hamburg-Eppendorf, Hamburg, Germany
| | - Lena Möbus
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE,), Faculty of Medicine and Health Technology, Tampere University, 33520, Tampere, Finland
| | - Simon Bub
- Anatomical Institute, Kiel University, Germany
| | | | - Felix Elsner
- Institute of Pathology, University Hospital Erlangen, Erlangen, Germany
| | - Volker Spindler
- Department of Biomedicine, University of Basel, Switzerland
- Institute of Anatomy and Experimental Morphology, University Clinic Hamburg-Eppendorf, Hamburg, Germany
| | - Philipp Arnold
- Institute of Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| |
Collapse
|
27
|
Yuan Y, Li P, Li J, Zhao Q, Chang Y, He X. Protein lipidation in health and disease: molecular basis, physiological function and pathological implication. Signal Transduct Target Ther 2024; 9:60. [PMID: 38485938 PMCID: PMC10940682 DOI: 10.1038/s41392-024-01759-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/31/2023] [Accepted: 01/24/2024] [Indexed: 03/18/2024] Open
Abstract
Posttranslational modifications increase the complexity and functional diversity of proteins in response to complex external stimuli and internal changes. Among these, protein lipidations which refer to lipid attachment to proteins are prominent, which primarily encompassing five types including S-palmitoylation, N-myristoylation, S-prenylation, glycosylphosphatidylinositol (GPI) anchor and cholesterylation. Lipid attachment to proteins plays an essential role in the regulation of protein trafficking, localisation, stability, conformation, interactions and signal transduction by enhancing hydrophobicity. Accumulating evidence from genetic, structural, and biomedical studies has consistently shown that protein lipidation is pivotal in the regulation of broad physiological functions and is inextricably linked to a variety of diseases. Decades of dedicated research have driven the development of a wide range of drugs targeting protein lipidation, and several agents have been developed and tested in preclinical and clinical studies, some of which, such as asciminib and lonafarnib are FDA-approved for therapeutic use, indicating that targeting protein lipidations represents a promising therapeutic strategy. Here, we comprehensively review the known regulatory enzymes and catalytic mechanisms of various protein lipidation types, outline the impact of protein lipidations on physiology and disease, and highlight potential therapeutic targets and clinical research progress, aiming to provide a comprehensive reference for future protein lipidation research.
Collapse
Affiliation(s)
- Yuan Yuan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peiyuan Li
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianghui Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China.
| | - Ying Chang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China.
| | - Xingxing He
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China.
| |
Collapse
|
28
|
Ballestín A, Armocida D, Ribecco V, Seano G. Peritumoral brain zone in glioblastoma: biological, clinical and mechanical features. Front Immunol 2024; 15:1347877. [PMID: 38487525 PMCID: PMC10937439 DOI: 10.3389/fimmu.2024.1347877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/14/2024] [Indexed: 03/17/2024] Open
Abstract
Glioblastoma is a highly aggressive and invasive tumor that affects the central nervous system (CNS). With a five-year survival rate of only 6.9% and a median survival time of eight months, it has the lowest survival rate among CNS tumors. Its treatment consists of surgical resection, subsequent fractionated radiotherapy and concomitant and adjuvant chemotherapy with temozolomide. Despite the implementation of clinical interventions, recurrence is a common occurrence, with over 80% of cases arising at the edge of the resection cavity a few months after treatment. The high recurrence rate and location of glioblastoma indicate the need for a better understanding of the peritumor brain zone (PBZ). In this review, we first describe the main radiological, cellular, molecular and biomechanical tissue features of PBZ; and subsequently, we discuss its current clinical management, potential local therapeutic approaches and future prospects.
Collapse
Affiliation(s)
- Alberto Ballestín
- Tumor Microenvironment Laboratory, UMR3347 CNRS/U1021 INSERM, Institut Curie, Orsay, France
| | - Daniele Armocida
- Human Neurosciences Department, Neurosurgery Division, Sapienza University, Rome, Italy
| | - Valentino Ribecco
- Tumor Microenvironment Laboratory, UMR3347 CNRS/U1021 INSERM, Institut Curie, Orsay, France
| | - Giorgio Seano
- Tumor Microenvironment Laboratory, UMR3347 CNRS/U1021 INSERM, Institut Curie, Orsay, France
| |
Collapse
|
29
|
De Fazio E, Pittarello M, Gans A, Ghosh B, Slika H, Alimonti P, Tyler B. Intrinsic and Microenvironmental Drivers of Glioblastoma Invasion. Int J Mol Sci 2024; 25:2563. [PMID: 38473812 PMCID: PMC10932253 DOI: 10.3390/ijms25052563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/07/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
Gliomas are diffusely infiltrating brain tumors whose prognosis is strongly influenced by their extent of invasion into the surrounding brain tissue. While lower-grade gliomas present more circumscribed borders, high-grade gliomas are aggressive tumors with widespread brain infiltration and dissemination. Glioblastoma (GBM) is known for its high invasiveness and association with poor prognosis. Its low survival rate is due to the certainty of its recurrence, caused by microscopic brain infiltration which makes surgical eradication unattainable. New insights into GBM biology at the single-cell level have enabled the identification of mechanisms exploited by glioma cells for brain invasion. In this review, we explore the current understanding of several molecular pathways and mechanisms used by tumor cells to invade normal brain tissue. We address the intrinsic biological drivers of tumor cell invasion, by tackling how tumor cells interact with each other and with the tumor microenvironment (TME). We focus on the recently discovered neuronal niche in the TME, including local as well as distant neurons, contributing to glioma growth and invasion. We then address the mechanisms of invasion promoted by astrocytes and immune cells. Finally, we review the current literature on the therapeutic targeting of the molecular mechanisms of invasion.
Collapse
Affiliation(s)
- Emerson De Fazio
- Department of Medicine, Vita-Salute San Raffaele University School of Medicine, 20132 Milan, Italy; (E.D.F.); (P.A.)
| | - Matilde Pittarello
- Department of Medicine, Humanitas University School of Medicine, 20089 Rozzano, Italy;
| | - Alessandro Gans
- Department of Neurology, University of Milan, 20122 Milan, Italy;
| | - Bikona Ghosh
- School of Medicine and Surgery, Dhaka Medical College, Dhaka 1000, Bangladesh;
| | - Hasan Slika
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA;
| | - Paolo Alimonti
- Department of Medicine, Vita-Salute San Raffaele University School of Medicine, 20132 Milan, Italy; (E.D.F.); (P.A.)
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Betty Tyler
- Hunterian Neurosurgical Laboratory, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA;
| |
Collapse
|
30
|
Panic A, Moore J, Gallego-Perez D. Single clonal tracking on biomimetic microtextured platforms for real-time guided migration analysis of myeloid-derived suppressor cell dissemination characteristics ex vivo. Methods Cell Biol 2024; 184:97-103. [PMID: 38555161 DOI: 10.1016/bs.mcb.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
Current strategies to undermine the deleterious influence of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) are lacking effective clinical solutions, in large part, due to insufficient knowledge on susceptible cellular and molecular targets. We describe here the application of biomimetic microfabricated platforms designed to analyze migratory phenotypes of MDSCs in the tumor niche ex vivo, which may enable accelerated therapeutic discovery. By mimicking the guided structural cues present in the physiological architecture of the TME, aligned microtopography substrates can elucidate potential interventions on migratory phenotypes of MDSCs at the single clonal level. Coupled with cellular and molecular biology analysis tools, our approach employs real-time tracking analysis of cell motility to probe the dissemination characteristics of MDSCs under guided migration conditions. These methods allow us to identify cellular subpopulations of interest based on their disseminative and suppressive capabilities. By doing so, we illustrate the potential of applying microscale engineering tools, in concert with dynamic live cell imaging and bioanalysis methods to uncover novel exploitable motility targets for advancing cancer therapy discovery. The inherent simplicity and extended application to a variety of contexts in tumor-associated cell migration render this method widely accessible to existing biological laboratory conditions and interests.
Collapse
Affiliation(s)
- Ana Panic
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States
| | - Jordan Moore
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States
| | - Daniel Gallego-Perez
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States; Department of Surgery, The Ohio State University, Columbus, OH, United States.
| |
Collapse
|
31
|
Park JH, Hothi P, Lopez Garcia de Lomana A, Pan M, Calder R, Turkarslan S, Wu WJ, Lee H, Patel AP, Cobbs C, Huang S, Baliga NS. Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.02.578510. [PMID: 38370784 PMCID: PMC10871280 DOI: 10.1101/2024.02.02.578510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
Poor prognosis and drug resistance in glioblastoma (GBM) can result from cellular heterogeneity and treatment-induced shifts in phenotypic states of tumor cells, including dedifferentiation into glioma stem-like cells (GSCs). This rare tumorigenic cell subpopulation resists temozolomide, undergoes proneural-to-mesenchymal transition (PMT) to evade therapy, and drives recurrence. Through inference of transcriptional regulatory networks (TRNs) of patient-derived GSCs (PD-GSCs) at single-cell resolution, we demonstrate how the topology of transcription factor interaction networks drives distinct trajectories of cell state transitions in PD-GSCs resistant or susceptible to cytotoxic drug treatment. By experimentally testing predictions based on TRN simulations, we show that drug treatment drives surviving PD-GSCs along a trajectory of intermediate states, exposing vulnerability to potentiated killing by siRNA or a second drug targeting treatment-induced transcriptional programs governing non-genetic cell plasticity. Our findings demonstrate an approach to uncover TRN topology and use it to rationally predict combinatorial treatments that disrupts acquired resistance in GBM.
Collapse
Affiliation(s)
| | - Parvinder Hothi
- Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA
| | | | - Min Pan
- Institute for Systems Biology, Seattle, WA
| | | | | | - Wei-Ju Wu
- Institute for Systems Biology, Seattle, WA
| | - Hwahyung Lee
- Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA
| | - Anoop P Patel
- Department of Neurosurgery, Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC
- Center for Advanced Genomic Technologies, Duke University, Durham, NC
| | - Charles Cobbs
- Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA
| | - Sui Huang
- Institute for Systems Biology, Seattle, WA
| | - Nitin S Baliga
- Institute for Systems Biology, Seattle, WA
- Departments of Microbiology, Biology, and Molecular Engineering Sciences, University of Washington, Seattle, WA
| |
Collapse
|
32
|
Gondarenko E, Mazur D, Masliakova M, Ryabukha Y, Kasheverov I, Utkin Y, Tsetlin V, Shahparonov M, Kudryavtsev D, Antipova N. Subtype-Selective Peptide and Protein Neurotoxic Inhibitors of Nicotinic Acetylcholine Receptors Enhance Proliferation of Patient-Derived Glioblastoma Cell Lines. Toxins (Basel) 2024; 16:80. [PMID: 38393158 PMCID: PMC10891657 DOI: 10.3390/toxins16020080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/24/2024] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
Glioblastoma multiforme (GBM) is the most aggressive type of brain cancer, with a poor prognosis. GBM cells, which develop in the environment of neural tissue, often exploit neurotransmitters and their receptors to promote their own growth and invasion. Nicotinic acetylcholine receptors (nAChRs), which play a crucial role in central nervous system signal transmission, are widely represented in the brain, and GBM cells express several subtypes of nAChRs that are suggested to transmit signals from neurons, promoting tumor invasion and growth. Analysis of published GBM transcriptomes revealed spatial heterogeneity in nAChR subtype expression, and functional nAChRs of α1*, α7, and α9 subtypes are demonstrated in our work on several patient-derived GBM microsphere cultures and on the U87MG GBM cell line using subtype-selective neurotoxins and fluorescent calcium mobilization assay. The U87MG cell line shows reactions to nicotinic agonists similar to those of GBM patient-derived culture. Selective α1*, α7, and α9 nAChR neurotoxins stimulated cell growth in the presence of nicotinic agonists. Several cultivating conditions with varying growth factor content have been proposed and tested. The use of selective neurotoxins confirmed that cell cultures obtained from patients are representative GBM models, but the use of media containing fetal bovine serum can lead to alterations in nAChR expression and functioning.
Collapse
Affiliation(s)
- Elena Gondarenko
- Department of Molecular Neuroimmune Signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, 117997 Moscow, Russia; (E.G.); (I.K.); (V.T.); (D.K.)
| | - Diana Mazur
- Department of Functioning of Living Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, 117997 Moscow, Russia; (D.M.); (M.M.); (Y.R.); (M.S.); (N.A.)
| | - Marina Masliakova
- Department of Functioning of Living Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, 117997 Moscow, Russia; (D.M.); (M.M.); (Y.R.); (M.S.); (N.A.)
| | - Yana Ryabukha
- Department of Functioning of Living Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, 117997 Moscow, Russia; (D.M.); (M.M.); (Y.R.); (M.S.); (N.A.)
| | - Igor Kasheverov
- Department of Molecular Neuroimmune Signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, 117997 Moscow, Russia; (E.G.); (I.K.); (V.T.); (D.K.)
| | - Yuri Utkin
- Department of Molecular Neuroimmune Signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, 117997 Moscow, Russia; (E.G.); (I.K.); (V.T.); (D.K.)
| | - Victor Tsetlin
- Department of Molecular Neuroimmune Signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, 117997 Moscow, Russia; (E.G.); (I.K.); (V.T.); (D.K.)
| | - Mikhail Shahparonov
- Department of Functioning of Living Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, 117997 Moscow, Russia; (D.M.); (M.M.); (Y.R.); (M.S.); (N.A.)
| | - Denis Kudryavtsev
- Department of Molecular Neuroimmune Signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, 117997 Moscow, Russia; (E.G.); (I.K.); (V.T.); (D.K.)
- Department of Biology and General Genetics, I.M. Sechenov First Moscow State Medical University, 119048 Moscow, Russia
| | - Nadine Antipova
- Department of Functioning of Living Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, 117997 Moscow, Russia; (D.M.); (M.M.); (Y.R.); (M.S.); (N.A.)
| |
Collapse
|
33
|
Ponti AK, Silver DJ, Hine C, Lathia JD. Should I stay or should I go? Transsulfuration influences invasion and growth in glioblastoma. J Clin Invest 2024; 134:e176879. [PMID: 38299594 PMCID: PMC10836793 DOI: 10.1172/jci176879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2024] Open
Abstract
A major challenge in treating patients with glioblastoma is the inability to eliminate highly invasive cells with chemotherapy, radiation, or surgical resection. As cancer cells face the issue of replicating or invading neighboring tissue, they rewire their metabolism in a concerted effort to support necessary cellular processes and account for altered nutrient abundance. In this issue of the JCI, Garcia et al. compared an innovative 3D hydrogel-based invasion device to regional patient biopsies through a comprehensive multiomics-based approach paired with a CRISPR knockout screen. Their findings elucidate a role for cystathionine γ-lyase (CTH), an enzyme in the transsulfuration pathway, as a means of regulating the cellular response to oxidative stress. CTH-mediated conversion of cystathionine to cysteine was necessary for regulating reactive oxygen species to support invasion. Meanwhile, inhibition of CTH suppressed the invasive glioblastoma phenotype. However, inhibiting CTH resulted in a larger overall tumor mass. These findings suggest that targeting the transsulfuration pathway may serve as a means of redirecting glioblastoma to proliferate or invade.
Collapse
Affiliation(s)
- András K Ponti
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine and Case Western Reserve University, Cleveland, Ohio, USA
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA
| | - Daniel J Silver
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Cleveland, Ohio, USA
- Department of Pathology, Cleveland Clinic Lerner College of Medicine and Case Western Reserve University, Cleveland, Ohio, USA
| | - Christopher Hine
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine and Case Western Reserve University, Cleveland, Ohio, USA
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Justin D Lathia
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine and Case Western Reserve University, Cleveland, Ohio, USA
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| |
Collapse
|
34
|
Xiong Z, Raphael I, Olin M, Okada H, Li X, Kohanbash G. Glioblastoma vaccines: past, present, and opportunities. EBioMedicine 2024; 100:104963. [PMID: 38183840 PMCID: PMC10808938 DOI: 10.1016/j.ebiom.2023.104963] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 12/21/2023] [Accepted: 12/24/2023] [Indexed: 01/08/2024] Open
Abstract
Glioblastoma (GBM) is one of the most lethal central nervous systems (CNS) tumours in adults. As supplements to standard of care (SOC), various immunotherapies improve the therapeutic effect in other cancers. Among them, tumour vaccines can serve as complementary monotherapy or boost the clinical efficacy with other immunotherapies, such as immune checkpoint blockade (ICB) and chimeric antigen receptor T cells (CAR-T) therapy. Previous studies in GBM therapeutic vaccines have suggested that few neoantigens could be targeted in GBM due to low mutation burden, and single-peptide therapeutic vaccination had limited efficacy in tumour control as monotherapy. Combining diverse antigens, including neoantigens, tumour-associated antigens (TAAs), and pathogen-derived antigens, and optimizing vaccine design or vaccination strategy may help with clinical efficacy improvement. In this review, we discussed current GBM therapeutic vaccine platforms, evaluated and potential antigenic targets, current challenges, and perspective opportunities for efficacy improvement.
Collapse
Affiliation(s)
- Zujian Xiong
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA; Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China
| | - Itay Raphael
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA
| | - Michael Olin
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Hideho Okada
- Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA
| | - Xuejun Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan 410008 PR China.
| | - Gary Kohanbash
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
| |
Collapse
|
35
|
Cirotti C, Taddei I, Contadini C, Di Girolamo C, Pepe G, De Bardi M, Borsellino G, Helmer-Citterich M, Barilà D. NRF2 connects Src tyrosine kinase to ferroptosis resistance in glioblastoma. Life Sci Alliance 2024; 7:e202302205. [PMID: 37879937 PMCID: PMC10599979 DOI: 10.26508/lsa.202302205] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 10/16/2023] [Accepted: 10/16/2023] [Indexed: 10/27/2023] Open
Abstract
Glioblastoma is a severe brain tumor characterized by an extremely poor survival rate of patients. Glioblastoma cancer cells escape to standard therapeutic protocols consisting of a combination of ionizing radiation and temozolomide alkylating drugs that trigger DNA damage by rewiring of signaling pathways. In recent years, the up-regulation of factors that counteract ferroptosis has been highlighted as a major driver of cancer resistance to ionizing radiation, although the molecular connection between the activation of oncogenic signaling and the modulation of ferroptosis has not been clarified yet. Here, we provide the first evidence for a molecular connection between the constitutive activation of tyrosine kinases and resistance to ferroptosis. Src tyrosine kinase, a central hub on which deregulated receptor tyrosine kinase signaling converge in cancer, leads to the stabilization and activation of NRF2 pathway, thus promoting resistance to ionizing radiation-induced ferroptosis. These data suggest that the up-regulation of the Src-NRF2 axis may represent a vulnerability for combined strategies that, by targeting ferroptosis resistance, enhance radiation sensitivity in glioblastoma.
Collapse
Affiliation(s)
- Claudia Cirotti
- Department of Biology, University of Rome "Tor Vergata," Rome, Italy
- Laboratory of Cell Signaling, IRCCS-Fondazione Santa Lucia, Rome, Italy
| | - Irene Taddei
- Department of Biology, University of Rome "Tor Vergata," Rome, Italy
- Laboratory of Cell Signaling, IRCCS-Fondazione Santa Lucia, Rome, Italy
| | - Claudia Contadini
- Department of Biology, University of Rome "Tor Vergata," Rome, Italy
- Laboratory of Cell Signaling, IRCCS-Fondazione Santa Lucia, Rome, Italy
- UOSD Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | | | - Gerardo Pepe
- Department of Biology, University of Rome "Tor Vergata," Rome, Italy
| | - Marco De Bardi
- Neuroimmunology Unit, Experimental Neuroscience, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Giovanna Borsellino
- Neuroimmunology Unit, Experimental Neuroscience, IRCCS Fondazione Santa Lucia, Rome, Italy
| | | | - Daniela Barilà
- Department of Biology, University of Rome "Tor Vergata," Rome, Italy
- Laboratory of Cell Signaling, IRCCS-Fondazione Santa Lucia, Rome, Italy
| |
Collapse
|
36
|
Patel KS, Tessema KK, Kawaguchi R, Dudley L, Alvarado AG, Muthukrishnan SD, Perryman T, Hagiwara A, Swarup V, Liau LM, Wang AC, Yong W, Geschwind DH, Nakano I, Goldman SA, Everson RG, Ellingson BM, Kornblum HI. Single-nucleus expression characterization of non-enhancing region of recurrent high-grade glioma. Neurooncol Adv 2024; 6:vdae005. [PMID: 38616896 PMCID: PMC11012612 DOI: 10.1093/noajnl/vdae005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2024] Open
Abstract
Background Non-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma. Methods We leveraged single-nucleus RNA sequencing on 15 specimens from recurrent high-grade gliomas (n = 5) to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining to validate RNA findings. Results Tumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched in mesenchymal-like states. NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki-67 staining. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Our findings in recurrent GBM paralleled some of the findings in a re-analysis of a dataset from primary GBM. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and cell-mediated immune response, but increased glioma-to-nonpathological cell interactions. Conclusions This comprehensive analysis illustrates differing tumor and nontumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. These findings also support the aggressive approach to resection of tumor-bearing NE regions.
Collapse
Affiliation(s)
- Kunal S Patel
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Kaleab K Tessema
- The Intellectual and Developmental Disabilities Research Center and Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Riki Kawaguchi
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Lindsey Dudley
- The Intellectual and Developmental Disabilities Research Center and Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Alvaro G Alvarado
- The Intellectual and Developmental Disabilities Research Center and Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Sree Deepthi Muthukrishnan
- The Intellectual and Developmental Disabilities Research Center and Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Travis Perryman
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Akifumi Hagiwara
- UCLA Brain Tumor Imaging Laboratory (BTIL), Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Vivek Swarup
- Department of Neurobiology and Behavior, UCI School of Biological Sciences, Irvine, California, USA
| | - Linda M Liau
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Anthony C Wang
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - William Yong
- Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Daniel H Geschwind
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Ichiro Nakano
- Department of Neurosurgery, Hokuto Social Medical Corporation, Hokuto Hospital, Hokuto, Japan
| | - Steven A Goldman
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
- Faculty of Health and Medical Sciences, Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark
| | - Richard G Everson
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Benjamin M Ellingson
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Harley I Kornblum
- The Intellectual and Developmental Disabilities Research Center and Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
- Departments of Pediatrics, Psychiatry, and Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| |
Collapse
|
37
|
Bentaberry-Rosa A, Nicaise Y, Delmas C, Gouazé-Andersson V, Cohen-Jonathan-Moyal E, Seva C. Overexpression of Growth Differentiation Factor 15 in Glioblastoma Stem Cells Promotes Their Radioresistance. Cancers (Basel) 2023; 16:27. [PMID: 38201456 PMCID: PMC10778311 DOI: 10.3390/cancers16010027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/15/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open
Abstract
GSCs play an important role in GBM recurrence. Understanding the resistance mechanisms in these cells is therefore crucial for radiation therapy optimization. In this study, using patient-derived GSCs, we demonstrate that GDF15, a cytokine belonging to the TGF-β superfamily, is regulated by irradiation (IR) and the transcription factor WWTR1/TAZ. Blocking WWTR1/TAZ using specific siRNAs significantly reduces GDF15 basal expression and reverses the upregulation of this cytokine induced by IR. Furthermore, we demonstrate that GDF15 plays an important role in GSC radioresistance. Targeting GDF15 expression by siRNA in GSCs expressing high levels of GDF15 sensitizes the cells to IR. In addition, we also found that GDF15 expression is critical for GSC spheroid formation, as GDF15 knockdown significantly reduces the number of GSC neurospheres. This study suggests that GDF15 targeting in combination with radiotherapy may be a feasible approach in patients with GBM.
Collapse
Affiliation(s)
- Alexandre Bentaberry-Rosa
- Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, 31062 Toulouse, France; (A.B.-R.); (Y.N.); (C.D.); (V.G.-A.); (E.C.-J.-M.)
- IUCT-Oncopole, 31100 Toulouse, France
| | - Yvan Nicaise
- Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, 31062 Toulouse, France; (A.B.-R.); (Y.N.); (C.D.); (V.G.-A.); (E.C.-J.-M.)
| | - Caroline Delmas
- Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, 31062 Toulouse, France; (A.B.-R.); (Y.N.); (C.D.); (V.G.-A.); (E.C.-J.-M.)
- IUCT-Oncopole, 31100 Toulouse, France
| | - Valérie Gouazé-Andersson
- Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, 31062 Toulouse, France; (A.B.-R.); (Y.N.); (C.D.); (V.G.-A.); (E.C.-J.-M.)
- IUCT-Oncopole, 31100 Toulouse, France
| | - Elizabeth Cohen-Jonathan-Moyal
- Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, 31062 Toulouse, France; (A.B.-R.); (Y.N.); (C.D.); (V.G.-A.); (E.C.-J.-M.)
- IUCT-Oncopole, 31100 Toulouse, France
| | - Catherine Seva
- Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, 31062 Toulouse, France; (A.B.-R.); (Y.N.); (C.D.); (V.G.-A.); (E.C.-J.-M.)
| |
Collapse
|
38
|
Sajid RS, van Winden LJ, Diamandis P. Towards deciphering glioblastoma intra-tumoral heterogeneity: The importance of integrating multidimensional models. Proteomics 2023; 23:e2200401. [PMID: 37488996 DOI: 10.1002/pmic.202200401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 07/12/2023] [Accepted: 07/13/2023] [Indexed: 07/26/2023]
Abstract
Glioblastoma (GBM) is the most common and severe form of brain cancer among adults. Its aggressiveness is largely attributed to its complex and heterogeneous biology that despite maximal surgery and multimodal chemoradiation treatment, inevitably recurs. Traditional large-scale profiling approaches have contributed substantially to the understanding of patient-to-patient inter-tumoral differences in GBM. However, it is now clear that biological differences within an individual (intra-tumoral heterogeneity) are also a prominent factor in treatment resistance and recurrence of GBM and will likely require integration of data from multiple recently developed omics platforms to fully unravel. Here we dissect the growing geospatial model of GBM, which layers intra-tumoral heterogeneity on a GBM stem cell (GSC) precursor, single cell, and spatial level. We discuss potential unique and inter-dependant aspects of the model including potential discordances between observed genotypes and phenotypes in GBM.
Collapse
Affiliation(s)
- Rifat Shahriar Sajid
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Lennart J van Winden
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Phedias Diamandis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
- Laboratory Medicine Program, University Health Network, Toronto, Canada
- Princess Margaret Cancer Center, University Health Network, Toronto, Canada
| |
Collapse
|
39
|
Stringer BW, De Silva MI, Greenberg Z, Noreña Puerta A, Adams R, Milky B, Zabolocki M, van den Hurk M, Ebert LM, Fairly Bishop C, Conn SJ, Kichenadasse G, Michael MZ, Ormsby RJ, Poonoose S, Bardy C. Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma. SCIENCE ADVANCES 2023; 9:eadf1332. [PMID: 37878712 PMCID: PMC10599627 DOI: 10.1126/sciadv.adf1332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 09/21/2023] [Indexed: 10/27/2023]
Abstract
Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.
Collapse
Affiliation(s)
- Brett W. Stringer
- South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Manam Inushi De Silva
- South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Zarina Greenberg
- South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia
| | - Alejandra Noreña Puerta
- South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Robert Adams
- South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Bridget Milky
- South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Michael Zabolocki
- South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Mark van den Hurk
- South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia
| | - Lisa M. Ebert
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Christine Fairly Bishop
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Flinders Medical Centre, SA Health, Adelaide, SA, Australia
| | - Simon J. Conn
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Ganessan Kichenadasse
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Flinders Medical Centre, SA Health, Adelaide, SA, Australia
| | - Michael Z. Michael
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Flinders Medical Centre, SA Health, Adelaide, SA, Australia
| | - Rebecca J. Ormsby
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Santosh Poonoose
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Cedric Bardy
- South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| |
Collapse
|
40
|
Tora MS, Neill SG, Lakhina Y, Assed H, Zhang M, Nagarajan PP, Federici T, Gutierrez J, Hoang KB, Du Y, Lei K, Boulis NM. Tumor microenvironment in a minipig model of spinal cord glioma. J Transl Med 2023; 21:667. [PMID: 37752585 PMCID: PMC10523785 DOI: 10.1186/s12967-023-04531-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 09/15/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND Spinal cord glioma (SCG) is considered an orphan disease that lacks effective treatment options with margins that are surgically inaccessible and an overall paucity of literature on the topic. The tumor microenvironment is a critical factor to consider in treatment and modeling design, especially with respect to the unresectable tumor edge. Recently, our group developed a high-grade spinal cord glioma (SCG) model in Göttingen minipigs. METHODS Immunofluorescence and ELISA were performed to explore the microenvironmental features and inflammation cytokines in this minipig SCG model. Protein carbonyl assay and GSH/GSSG assay were analyzed in the core and edge lesions in the minipig SCG model. The primary core and edge cells proliferation rate were shown in vitro, and the xenograft model in vivo. RESULTS We identified an elevated Ki-67 proliferative index, vascular and pericyte markers, CD31 and desmin in the tumor edge as compared to the tumor core. In addition, we found that the tumor edge demonstrated increased pro-inflammatory and gliomagenic cytokines including TNF-α, IL-1β, and IL-6. Furthermore, the mediation of oxidative stress is upregulated in the tumor edge. Hypoxic markers had statistically significant increased staining in the tumor core, but were notably still present in the tumor edge. The edge cells cultures derived from SCG biopsy also demonstrated an increased proliferative rate compared to core cell cultures in a xenotransplantation model. CONCLUSIONS Our study demonstrates heterogeneity in microenvironmental features in our minipig model of high-grade SCG, with a phenotype at the edge showing increased oxidative stress, proliferation, inflammatory cytokines, neovascularization, and decreased but present staining for hypoxic markers. These findings support the utility of this model as a means for investigating therapeutic approaches targeting the more aggressive and surgically unresectable tumor border.
Collapse
Affiliation(s)
- Muhibullah S Tora
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Stewart G Neill
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Yuliya Lakhina
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Hemza Assed
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Michelle Zhang
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Purva P Nagarajan
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Thais Federici
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Juanmarco Gutierrez
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Kimberly B Hoang
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Yuhong Du
- Department of Pharmacology and Chemical Biology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Kecheng Lei
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA.
| | - Nicholas M Boulis
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA.
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
| |
Collapse
|
41
|
Jeon HM, Kim JY, Cho HJ, Lee WJ, Nguyen D, Kim SS, Oh YT, Kim HJ, Jung CW, Pinero G, Joshi T, Hambardzumyan D, Sakaguchi T, Hubert CG, McIntyre TM, Fine HA, Gladson CL, Wang B, Purow BW, Park JB, Park MJ, Nam DH, Lee J. Tissue factor is a critical regulator of radiation therapy-induced glioblastoma remodeling. Cancer Cell 2023; 41:1480-1497.e9. [PMID: 37451272 PMCID: PMC10530238 DOI: 10.1016/j.ccell.2023.06.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 02/28/2023] [Accepted: 06/20/2023] [Indexed: 07/18/2023]
Abstract
Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its microenvironment (TME) that promote radio-resistance and recurrence. Through a cell surface marker screen, we identified that CD142 (tissue factor or F3) is robustly induced in the senescence-associated β-galactosidase (SA-βGal)-positive GBM cells after irradiation. F3 promotes clonal expansion of irradiated SA-βGal+ GBM cells and orchestrates oncogenic TME remodeling by activating both tumor-autonomous signaling and extrinsic coagulation pathways. Intratumoral F3 signaling induces a mesenchymal-like cell state transition and elevated chemokine secretion. Simultaneously, F3-mediated focal hypercoagulation states lead to activation of tumor-associated macrophages (TAMs) and extracellular matrix (ECM) remodeling. A newly developed F3-targeting agent potently inhibits the aforementioned oncogenic events and impedes tumor relapse in vivo. These findings support F3 as a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues.
Collapse
Affiliation(s)
- Hye-Min Jeon
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jeong-Yub Kim
- Divisions of Radiation Cancer Research, Research Center for Radio-Senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hee Jin Cho
- Department of Biomedical Convergence Science and Technology, Kyungpook National University, Daegu, Korea
| | - Won Jun Lee
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Dayna Nguyen
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Sung Soo Kim
- Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea
| | - Young Taek Oh
- Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea
| | - Hee-Jin Kim
- Divisions of Radiation Cancer Research, Research Center for Radio-Senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Chan-Woong Jung
- Divisions of Radiation Cancer Research, Research Center for Radio-Senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Gonzalo Pinero
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Tanvi Joshi
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Takuya Sakaguchi
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Christopher G Hubert
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Thomas M McIntyre
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Howard A Fine
- Department of Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Candece L Gladson
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Bingcheng Wang
- Department of Medicine, MetroHealth Campus, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Benjamin W Purow
- Department of Neurology, UVA Cancer Center, University of Virginia Health System, Charlottesville, VA, USA
| | - Jong Bae Park
- Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea
| | - Myung Jin Park
- Divisions of Radiation Cancer Research, Research Center for Radio-Senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Do-Hyun Nam
- Institute for Refractory Cancer Research, Samsung Medical Center, Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Department of Neurosurgery Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeongwu Lee
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
| |
Collapse
|
42
|
García-Montaño LA, Licón-Muñoz Y, Martinez FJ, Keddari YR, Ziemke MK, Chohan MO, Piccirillo SG. Dissecting Intra-tumor Heterogeneity in the Glioblastoma Microenvironment Using Fluorescence-Guided Multiple Sampling. Mol Cancer Res 2023; 21:755-767. [PMID: 37255362 PMCID: PMC10390891 DOI: 10.1158/1541-7786.mcr-23-0048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/25/2023] [Accepted: 05/05/2023] [Indexed: 05/10/2023]
Abstract
The treatment of the most aggressive primary brain tumor in adults, glioblastoma (GBM), is challenging due to its heterogeneous nature, invasive potential, and poor response to chemo- and radiotherapy. As a result, GBM inevitably recurs and only a few patients survive 5 years post-diagnosis. GBM is characterized by extensive phenotypic and genetic heterogeneity, creating a diversified genetic landscape and a network of biological interactions between subclones, ultimately promoting tumor growth and therapeutic resistance. This includes spatial and temporal changes in the tumor microenvironment, which influence cellular and molecular programs in GBM and therapeutic responses. However, dissecting phenotypic and genetic heterogeneity at spatial and temporal levels is extremely challenging, and the dynamics of the GBM microenvironment cannot be captured by analysis of a single tumor sample. In this review, we discuss the current research on GBM heterogeneity, in particular, the utility and potential applications of fluorescence-guided multiple sampling to dissect phenotypic and genetic intra-tumor heterogeneity in the GBM microenvironment, identify tumor and non-tumor cell interactions and novel therapeutic targets in areas that are key for tumor growth and recurrence, and improve the molecular classification of GBM.
Collapse
Affiliation(s)
- Leopoldo A. García-Montaño
- The Brain Tumor Translational Laboratory, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
- University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | - Yamhilette Licón-Muñoz
- The Brain Tumor Translational Laboratory, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
- University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | - Frank J. Martinez
- The Brain Tumor Translational Laboratory, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
- University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | - Yasine R. Keddari
- The Brain Tumor Translational Laboratory, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
- University of California, Merced, California
| | - Michael K. Ziemke
- Department of Neurosurgery, University of Mississippi Medical Center, Jackson, Mississippi
| | - Muhammad O. Chohan
- Department of Neurosurgery, University of Mississippi Medical Center, Jackson, Mississippi
| | - Sara G.M. Piccirillo
- The Brain Tumor Translational Laboratory, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
- University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| |
Collapse
|
43
|
Andrieux G, Das T, Griffin M, Straehle J, Paine SML, Beck J, Boerries M, Heiland DH, Smith SJ, Rahman R, Chakraborty S. Spatially resolved transcriptomic profiles reveal unique defining molecular features of infiltrative 5ALA-metabolizing cells associated with glioblastoma recurrence. Genome Med 2023; 15:48. [PMID: 37434262 PMCID: PMC10337060 DOI: 10.1186/s13073-023-01207-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 06/26/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Spatiotemporal heterogeneity originating from genomic and transcriptional variation was found to contribute to subtype switching in isocitrate dehydrogenase-1 wild-type glioblastoma (GBM) prior to and upon recurrence. Fluorescence-guided neurosurgical resection utilizing 5-aminolevulinic acid (5ALA) enables intraoperative visualization of infiltrative tumors outside the magnetic resonance imaging contrast-enhanced regions. The cell population and functional status of tumor responsible for enhancing 5ALA-metabolism to fluorescence-active PpIX remain elusive. The close spatial proximity of 5ALA-metabolizing (5ALA +) cells to residual disease remaining post-surgery renders 5ALA + biology an early a priori proxy of GBM recurrence, which is poorly understood. METHODS We performed spatially resolved bulk RNA profiling (SPRP) analysis of unsorted Core, Rim, Invasive margin tissue, and FACS-isolated 5ALA + /5ALA - cells from the invasive margin across IDH-wt GBM patients (N = 10) coupled with histological, radiographic, and two-photon excitation fluorescence microscopic analyses. Deconvolution of SPRP followed by functional analyses was performed using CIBEROSRTx and UCell enrichment algorithms, respectively. We further investigated the spatial architecture of 5ALA + enriched regions by analyzing spatial transcriptomics from an independent IDH-wt GBM cohort (N = 16). Lastly, we performed survival analysis using Cox Proportinal-Hazards model on large GBM cohorts. RESULTS SPRP analysis integrated with single-cell and spatial transcriptomics uncovered that the GBM molecular subtype heterogeneity is likely to manifest regionally in a cell-type-specific manner. Infiltrative 5ALA + cell population(s) harboring transcriptionally concordant GBM and myeloid cells with mesenchymal subtype, -active wound response, and glycolytic metabolic signature, was shown to reside within the invasive margin spatially distinct from the tumor core. The spatial co-localization of the infiltrating MES GBM and myeloid cells within the 5ALA + region indicates PpIX fluorescence can effectively be utilized to resect the immune reactive zone beyond the tumor core. Finally, 5ALA + gene signatures were associated with poor survival and recurrence in GBM, signifying that the transition from primary to recurrent GBM is not discrete but rather a continuum whereby primary infiltrative 5ALA + remnant tumor cells more closely resemble the eventual recurrent GBM. CONCLUSIONS Elucidating the unique molecular and cellular features of the 5ALA + population within tumor invasive margin opens up unique possibilities to develop more effective treatments to delay or block GBM recurrence, and warrants commencement of such treatments as early as possible post-surgical resection of the primary neoplasm.
Collapse
Affiliation(s)
- Geoffroy Andrieux
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tonmoy Das
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Systems Cell-Signaling Laboratory, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - Michaela Griffin
- Children's Brain Tumour Research Centre, Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK
| | - Jakob Straehle
- Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany
| | - Simon M L Paine
- Children's Brain Tumour Research Centre, Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK
| | - Jürgen Beck
- Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany
| | - Melanie Boerries
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dieter H Heiland
- Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Stuart J Smith
- Children's Brain Tumour Research Centre, Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK
| | - Ruman Rahman
- Children's Brain Tumour Research Centre, Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK.
| | - Sajib Chakraborty
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg Faculty of Medicine, University of Freiburg, Freiburg, Germany.
- Systems Cell-Signaling Laboratory, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh.
| |
Collapse
|
44
|
Contadini C, Cirotti C, Carbone A, Norouzi M, Cianciusi A, Crespan E, Perini C, Maga G, Barilà D, Musumeci F, Schenone S. Identification and Biological Characterization of the Pyrazolo[3,4- d]pyrimidine Derivative SI388 Active as Src Inhibitor. Pharmaceuticals (Basel) 2023; 16:958. [PMID: 37513870 PMCID: PMC10384936 DOI: 10.3390/ph16070958] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/27/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open
Abstract
Src is a non-receptor tyrosine kinase (TK) whose involvement in cancer, including glioblastoma (GBM), has been extensively demonstrated. In this context, we started from our in-house library of pyrazolo[3,4-d]pyrimidines that are active as Src and/or Bcr-Abl TK inhibitors and performed a lead optimization study to discover a new generation derivative that is suitable for Src kinase targeting. We synthesized a library of 19 compounds, 2a-s. Among these, compound 2a (SI388) was identified as the most potent Src inhibitor. Based on the cell-free results, we investigated the effect of SI388 in 2D and 3D GBM cellular models. Interestingly, SI388 significantly inhibits Src kinase, and therefore affects cell viability, tumorigenicity and enhances cancer cell sensitivity to ionizing radiation.
Collapse
Affiliation(s)
- Claudia Contadini
- Laboratory of Cell Signaling, IRCCS-Fondazione Santa Lucia, 00179 Rome, Italy
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Claudia Cirotti
- Laboratory of Cell Signaling, IRCCS-Fondazione Santa Lucia, 00179 Rome, Italy
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Anna Carbone
- Department of Pharmacy, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
| | - Mehrdad Norouzi
- Laboratory of Cell Signaling, IRCCS-Fondazione Santa Lucia, 00179 Rome, Italy
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Annarita Cianciusi
- Department of Pharmacy, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
| | - Emmanuele Crespan
- Institute of Molecular Genetics (IGM), IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy
| | - Cecilia Perini
- Institute of Molecular Genetics (IGM), IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy
| | - Giovanni Maga
- Institute of Molecular Genetics (IGM), IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy
| | - Daniela Barilà
- Laboratory of Cell Signaling, IRCCS-Fondazione Santa Lucia, 00179 Rome, Italy
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Francesca Musumeci
- Department of Pharmacy, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
| | - Silvia Schenone
- Department of Pharmacy, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy
| |
Collapse
|
45
|
Eckerdt F, Platanias LC. Emerging Role of Glioma Stem Cells in Mechanisms of Therapy Resistance. Cancers (Basel) 2023; 15:3458. [PMID: 37444568 PMCID: PMC10340782 DOI: 10.3390/cancers15133458] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 06/14/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023] Open
Abstract
Since their discovery at the beginning of this millennium, glioma stem cells (GSCs) have sparked extensive research and an energetic scientific debate about their contribution to glioblastoma (GBM) initiation, progression, relapse, and resistance. Different molecular subtypes of GBM coexist within the same tumor, and they display differential sensitivity to chemotherapy. GSCs contribute to tumor heterogeneity and recapitulate pathway alterations described for the three GBM subtypes found in patients. GSCs show a high degree of plasticity, allowing for interconversion between different molecular GBM subtypes, with distinct proliferative potential, and different degrees of self-renewal and differentiation. This high degree of plasticity permits adaptation to the environmental changes introduced by chemo- and radiation therapy. Evidence from mouse models indicates that GSCs repopulate brain tumors after therapeutic intervention, and due to GSC plasticity, they reconstitute heterogeneity in recurrent tumors. GSCs are also inherently resilient to standard-of-care therapy, and mechanisms of resistance include enhanced DNA damage repair, MGMT promoter demethylation, autophagy, impaired induction of apoptosis, metabolic adaptation, chemoresistance, and immune evasion. The remarkable oncogenic properties of GSCs have inspired considerable interest in better understanding GSC biology and functions, as they might represent attractive targets to advance the currently limited therapeutic options for GBM patients. This has raised expectations for the development of novel targeted therapeutic approaches, including targeting GSC plasticity, chimeric antigen receptor T (CAR T) cells, and oncolytic viruses. In this review, we focus on the role of GSCs as drivers of GBM and therapy resistance, and we discuss how insights into GSC biology and plasticity might advance GSC-directed curative approaches.
Collapse
Affiliation(s)
- Frank Eckerdt
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA
- Division of Hematology-Oncology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Leonidas C. Platanias
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA
- Division of Hematology-Oncology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA
- Medicine Service, Jesse Brown VA Medical Center, Chicago, IL 60612, USA
| |
Collapse
|
46
|
Kim JS, Shin MJ, Lee SY, Kim DK, Choi KU, Suh DS, Kim D, Kim JH. CD109 Promotes Drug Resistance in A2780 Ovarian Cancer Cells by Regulating the STAT3-NOTCH1 Signaling Axis. Int J Mol Sci 2023; 24:10306. [PMID: 37373457 DOI: 10.3390/ijms241210306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/05/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy owing to relapse caused by resistance to chemotherapy. We previously reported that cluster of differentiation 109 (CD109) expression is positively correlated with poor prognosis and chemoresistance in patients with EOC. To further explore the role of CD109 in EOC, we explored the signaling mechanism of CD109-induced drug resistance. We found that CD109 expression was upregulated in doxorubicin-resistant EOC cells (A2780-R) compared with that in their parental cells. In EOC cells (A2780 and A2780-R), the expression level of CD109 was positively correlated with the expression level of ATP-binding cassette (ABC) transporters, such as ABCB1 and ABCG2, and paclitaxel (PTX) resistance. Using a xenograft mouse model, it was confirmed that PTX administration in xenografts of CD109-silenced A2780-R cells significantly attenuated in vivo tumor growth. The treatment of CD109-overexpressed A2780 cells with cryptotanshinone (CPT), a signal transducer and activator of transcription 3 (STAT3) inhibitor, inhibited the CD109 overexpression-induced activation of STAT3 and neurogenic locus notch homolog protein 1 (NOTCH1), suggesting a STAT3-NOTCH1 signaling axis. The combined treatment of CD109-overexpressed A2780 cells with CPT and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), a NOTCH inhibitor, markedly abrogated PTX resistance. These results suggest that CD109 plays a key role in the acquisition of drug resistance by activating the STAT3-NOTCH1 signaling axis in patients with EOC.
Collapse
Affiliation(s)
- Jun Se Kim
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Min Joo Shin
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Seo Yul Lee
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | | | - Kyung-Un Choi
- Department of Pathology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Dong-Soo Suh
- Department of Obstetrics and Gynecology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Dayea Kim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu 41061, Republic of Korea
| | - Jae Ho Kim
- Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| |
Collapse
|
47
|
Pontes B, Mendes FA. Mechanical Properties of Glioblastoma: Perspectives for YAP/TAZ Signaling Pathway and Beyond. Diseases 2023; 11:86. [PMID: 37366874 DOI: 10.3390/diseases11020086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/06/2023] [Accepted: 06/12/2023] [Indexed: 06/28/2023] Open
Abstract
Glioblastoma is a highly aggressive brain tumor with a poor prognosis. Recent studies have suggested that mechanobiology, the study of how physical forces influence cellular behavior, plays an important role in glioblastoma progression. Several signaling pathways, molecules, and effectors, such as focal adhesions, stretch-activated ion channels, or membrane tension variations, have been studied in this regard. Also investigated are YAP/TAZ, downstream effectors of the Hippo pathway, which is a key regulator of cell proliferation and differentiation. In glioblastoma, YAP/TAZ have been shown to promote tumor growth and invasion by regulating genes involved in cell adhesion, migration, and extracellular matrix remodeling. YAP/TAZ can be activated by mechanical cues such as cell stiffness, matrix rigidity, and cell shape changes, which are all altered in the tumor microenvironment. Furthermore, YAP/TAZ have been shown to crosstalk with other signaling pathways, such as AKT, mTOR, and WNT, which are dysregulated in glioblastoma. Thus, understanding the role of mechanobiology and YAP/TAZ in glioblastoma progression could provide new insights into the development of novel therapeutic strategies. Targeting YAP/TAZ and mechanotransduction pathways in glioblastoma may offer a promising approach to treating this deadly disease.
Collapse
Affiliation(s)
- Bruno Pontes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Fabio A Mendes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| |
Collapse
|
48
|
Noorani I, Sidlauskas K, Pellow S, Savage R, Norman JL, Chatelet DS, Fabian M, Grundy P, Ching J, Nicoll JAR, Boche D. Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins. Brain Commun 2023; 5:fcad176. [PMID: 37324244 PMCID: PMC10265726 DOI: 10.1093/braincomms/fcad176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/19/2023] [Accepted: 06/01/2023] [Indexed: 06/17/2023] Open
Abstract
Glioblastoma is a devastating brain cancer for which effective treatments are required. Tumour-associated microglia and macrophages promote glioblastoma growth in an immune-suppressed microenvironment. Most recurrences occur at the invasive margin of the surrounding brain, yet the relationships between microglia/macrophage phenotypes, T cells and programmed death-ligand 1 (an immune checkpoint) across human glioblastoma regions are understudied. In this study, we performed a quantitative immunohistochemical analysis of 15 markers of microglia/macrophage phenotypes (including anti-inflammatory markers triggering receptor expressed on myeloid cells 2 and CD163, and the low-affinity-activating receptor CD32a), T cells, natural killer cells and programmed death-ligand 1, in 59 human IDH1-wild-type glioblastoma multi-regional samples (n = 177; 1 sample at tumour core, 2 samples at the margins: the infiltrating zone and leading edge). Assessment was made for the prognostic value of markers; the results were validated in an independent cohort. Microglia/macrophage motility and activation (Iba1, CD68), programmed death-ligand 1 and CD4+ T cells were reduced, and homeostatic microglia (P2RY12) were increased in the invasive margins compared with the tumour core. There were significant positive correlations between microglia/macrophage markers CD68 (phagocytic)/triggering receptor expressed on myeloid cells 2 (anti-inflammatory) and CD8+ T cells in the invasive margins but not in the tumour core (P < 0.01). Programmed death-ligand 1 expression was associated with microglia/macrophage markers (including anti-inflammatory) CD68, CD163, CD32a and triggering receptor expressed on myeloid cells 2, only in the leading edge of glioblastomas (P < 0.01). Similarly, there was a positive correlation between programmed death-ligand 1 expression and CD8+ T-cell infiltration in the leading edge (P < 0.001). There was no relationship between CD64 (a receptor for autoreactive T-cell responses) and CD8+/CD4+ T cells, or between the microglia/macrophage antigen presentation marker HLA-DR and microglial motility (Iba1) in the tumour margins. Natural killer cell infiltration (CD335+) correlated with CD8+ T cells and with CD68/CD163/triggering receptor expressed on myeloid cells 2 anti-inflammatory microglia/macrophages at the leading edge. In an independent large glioblastoma cohort with transcriptomic data, positive correlations between anti-inflammatory microglia/macrophage markers (triggering receptor expressed on myeloid cells 2, CD163 and CD32a) and CD4+/CD8+/programmed death-ligand 1 RNA expression were validated (P < 0.001). Finally, multivariate analysis showed that high triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the leading edge were significantly associated with poorer overall patient survival (hazard ratio = 2.05, 3.42 and 2.11, respectively), independent of clinical variables. In conclusion, anti-inflammatory microglia/macrophages, CD8+ T cells and programmed death-ligand 1 are correlated in the invasive margins of glioblastoma, consistent with immune-suppressive interactions. High triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the human glioblastoma leading edge are predictors of poorer overall survival. Given substantial interest in targeting microglia/macrophages, together with immune checkpoint inhibitors in cancer, these data have major clinical implications.
Collapse
Affiliation(s)
- Imran Noorani
- Department of Neuromuscular Diseases, The Francis Crick Institute and University College London, London NW1 1AT, UK
- Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London SO16 6AQ, UK
| | - Kastytis Sidlauskas
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Sean Pellow
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Reece Savage
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Jeannette L Norman
- Histochemistry Research Unit, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - David S Chatelet
- Biomedical Imaging Unit, Southampton General Hospital, University of Southampton, Southampton, UK
| | - Mark Fabian
- Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Paul Grundy
- Department of Neurosurgery, Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Jeng Ching
- Department of Neurosurgery, Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - James A R Nicoll
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Delphine Boche
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| |
Collapse
|
49
|
Higginbottom SL, Tomaskovic-Crook E, Crook JM. Considerations for modelling diffuse high-grade gliomas and developing clinically relevant therapies. Cancer Metastasis Rev 2023; 42:507-541. [PMID: 37004686 PMCID: PMC10348989 DOI: 10.1007/s10555-023-10100-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 03/16/2023] [Indexed: 04/04/2023]
Abstract
Diffuse high-grade gliomas contain some of the most dangerous human cancers that lack curative treatment options. The recent molecular stratification of gliomas by the World Health Organisation in 2021 is expected to improve outcomes for patients in neuro-oncology through the development of treatments targeted to specific tumour types. Despite this promise, research is hindered by the lack of preclinical modelling platforms capable of recapitulating the heterogeneity and cellular phenotypes of tumours residing in their native human brain microenvironment. The microenvironment provides cues to subsets of glioma cells that influence proliferation, survival, and gene expression, thus altering susceptibility to therapeutic intervention. As such, conventional in vitro cellular models poorly reflect the varied responses to chemotherapy and radiotherapy seen in these diverse cellular states that differ in transcriptional profile and differentiation status. In an effort to improve the relevance of traditional modelling platforms, recent attention has focused on human pluripotent stem cell-based and tissue engineering techniques, such as three-dimensional (3D) bioprinting and microfluidic devices. The proper application of these exciting new technologies with consideration of tumour heterogeneity and microenvironmental interactions holds potential to develop more applicable models and clinically relevant therapies. In doing so, we will have a better chance of translating preclinical research findings to patient populations, thereby addressing the current derisory oncology clinical trial success rate.
Collapse
Affiliation(s)
- Sarah L Higginbottom
- Intelligent Polymer Research Institute, AIIM Facility, Innovation Campus, University of Wollongong, Fairy Meadow, NSW, 2519, Australia
- Arto Hardy Family Biomedical Innovation Hub, Chris O'Brien Lifehouse, Camperdown, NSW, 2050, Australia
| | - Eva Tomaskovic-Crook
- Intelligent Polymer Research Institute, AIIM Facility, Innovation Campus, University of Wollongong, Fairy Meadow, NSW, 2519, Australia.
- Arto Hardy Family Biomedical Innovation Hub, Chris O'Brien Lifehouse, Camperdown, NSW, 2050, Australia.
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia.
| | - Jeremy M Crook
- Intelligent Polymer Research Institute, AIIM Facility, Innovation Campus, University of Wollongong, Fairy Meadow, NSW, 2519, Australia.
- Arto Hardy Family Biomedical Innovation Hub, Chris O'Brien Lifehouse, Camperdown, NSW, 2050, Australia.
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia.
| |
Collapse
|
50
|
Fan Y, Gao Z, Xu J, Wang H, Guo Q, Li B, Li M, Xu H, Qi Y, Zhao S, Qiu W, Pan Z, Wang Q, Xue H, Zhao R, Guo X, Li G. SPI1-mediated MIR222HG transcription promotes proneural-to-mesenchymal transition of glioma stem cells and immunosuppressive polarization of macrophages. Theranostics 2023; 13:3310-3329. [PMID: 37351164 PMCID: PMC10283056 DOI: 10.7150/thno.82590] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 05/07/2023] [Indexed: 06/24/2023] Open
Abstract
Background: Glioma stem cells (GSCs) are a key factor in glioblastoma (GBM) development and treatment resistance. GSCs can be divided into the mesenchymal (MES) and proneural (PN) subtypes, and these two subtypes of GSCs can undergo interconversion under certain conditions. MES GSCs have higher malignancy and radioresistance and are closely associated with an immunosuppressive microenvironment. Long noncoding RNAs (lncRNAs) play a broad role in GBM, while the role of GSCs subtype remains unknown. Methods: We performed RNA sequencing to explore the lncRNA expression profile in MES- and PN-subtype GBM tissues. The biological function of a host gene-MIR222HG-in GBM development was confirmed in vitro and in vivo. Specifically, RNA sequencing, RNA pulldown, mass spectrometry, RIP, ChIP, luciferase reporter assays and Co-IP were performed. Results: MIR222HG, the expression of which can be induced by SPI1, has high levels in MES GBM tissues. Functionally, we demonstrated that MIR222HG promotes the MES transition and radioresistance in GSCs in vivo and in vitro. Mechanistically, MIR222HG can bind to the YWHAE/HDAC5 complex to promote the MES transition of GSCs through H4 deacetylation. Moreover, cotranscribed miR221 and miR222 can be delivered to macrophages via exosomes to target SOCS3, causing immunosuppressive polarization. Finally, PLX-4720 sensitivity is associated with SPI1 expression and acts on MES GSCs to enhance radiosensitivity. Conclusions: This study demonstrates that targeting SPI1 to block transcription of the MIR222HG cluster helps to reduce radioresistance and combat the immunosuppressive microenvironment in GBM. PLX-4720 is a potential GBM drug and radiosensitizer.
Collapse
Affiliation(s)
- Yang Fan
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Zijie Gao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Jianye Xu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Huizhi Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Qindong Guo
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Boyan Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Ming Li
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
- Department of Neurosurgery, The Affiliated Taian City Central Hospital of Qingdao University, Taian 271000, Shandong, China
| | - Hao Xu
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
- Department of Neurosurgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, China
| | - Yanhua Qi
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Shulin Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Wei Qiu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Ziwen Pan
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Qingtong Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Hao Xue
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Rongrong Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Xing Guo
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| | - Gang Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China
| |
Collapse
|