Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations
Abstract Despite tremendous research efforts, successful targeting of aberrant tumor metabolism in clinical practice has remained elusive. Tumor heterogeneity and plasticity may play a role in the clinical failure of metabolism-targeting interventions for treating cancer patients. Moreover, compensa...
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01604-y |
| _version_ | 1827905208040030208 |
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| author | Emma Martell Helgi Kuzmychova Harshal Senthil Esha Kaul Chirayu R. Chokshi Chitra Venugopal Christopher M. Anderson Sheila K. Singh Tanveer Sharif |
| author_facet | Emma Martell Helgi Kuzmychova Harshal Senthil Esha Kaul Chirayu R. Chokshi Chitra Venugopal Christopher M. Anderson Sheila K. Singh Tanveer Sharif |
| author_sort | Emma Martell |
| collection | DOAJ |
| description | Abstract Despite tremendous research efforts, successful targeting of aberrant tumor metabolism in clinical practice has remained elusive. Tumor heterogeneity and plasticity may play a role in the clinical failure of metabolism-targeting interventions for treating cancer patients. Moreover, compensatory growth-related processes and adaptive responses exhibited by heterogeneous tumor subpopulations to metabolic inhibitors are poorly understood. Here, by using clinically-relevant patient-derived glioblastoma (GBM) cell models, we explore the cross-talk between glycolysis, autophagy, and senescence in maintaining tumor stemness. We found that stem cell-like GBM tumor subpopulations possessed higher basal levels of glycolytic activity and increased expression of several glycolysis-related enzymes including, GLUT1/SLC2A1, PFKP, ALDOA, GAPDH, ENO1, PKM2, and LDH, compared to their non-stem-like counterparts. Importantly, bioinformatics analysis also revealed that the mRNA expression of glycolytic enzymes positively correlates with stemness markers (CD133/PROM1 and SOX2) in patient GBM tumors. While treatment with glycolysis inhibitors induced senescence in stem cell-like GBM tumor subpopulations, as evidenced by increased β-galactosidase staining and upregulation of the cell cycle regulators p21Waf1/Cip1/CDKN1A and p16INK4A/CDKN2A, these cells maintained their aggressive stemness features and failed to undergo apoptotic cell death. Using various techniques including autophagy flux and EGFP-MAP1LC3B+ puncta formation analysis, we determined that inhibition of glycolysis led to the induction of autophagy in stem cell-like GBM tumor subpopulations, but not in their non-stem-like counterparts. Similarly, blocking autophagy in stem cell-like GBM tumor subpopulations induced senescence-associated growth arrest without hampering stemness capacity or inducing apoptosis while reciprocally upregulating glycolytic activity. Combinatorial treatment of stem cell-like GBM tumor subpopulations with autophagy and glycolysis inhibitors blocked the induction of senescence while drastically impairing their stemness capacity which drove cells towards apoptotic cell death. These findings identify a novel and complex compensatory interplay between glycolysis, autophagy, and senescence that helps maintain stemness in heterogeneous GBM tumor subpopulations and provides a survival advantage during metabolic stress. |
| first_indexed | 2024-03-13T00:38:43Z |
| format | Article |
| id | doaj.art-6a8d4e7ad8b24e438bb93abf59e42c2c |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-13T00:38:43Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-6a8d4e7ad8b24e438bb93abf59e42c2c2023-07-09T11:27:42ZengBMCActa Neuropathologica Communications2051-59602023-07-0111112010.1186/s40478-023-01604-yCompensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulationsEmma Martell0Helgi Kuzmychova1Harshal Senthil2Esha Kaul3Chirayu R. Chokshi4Chitra Venugopal5Christopher M. Anderson6Sheila K. Singh7Tanveer Sharif8Department of Pathology, Rady Faculty of Health Sciences, University of ManitobaDepartment of Pathology, Rady Faculty of Health Sciences, University of ManitobaDepartment of Pathology, Rady Faculty of Health Sciences, University of ManitobaFaculty of Science, University of ManitobaDepartment of Biochemistry, McMaster UniversityDepartment of Surgery, McMaster UniversityDepartment of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of ManitobaDepartment of Biochemistry, McMaster UniversityDepartment of Pathology, Rady Faculty of Health Sciences, University of ManitobaAbstract Despite tremendous research efforts, successful targeting of aberrant tumor metabolism in clinical practice has remained elusive. Tumor heterogeneity and plasticity may play a role in the clinical failure of metabolism-targeting interventions for treating cancer patients. Moreover, compensatory growth-related processes and adaptive responses exhibited by heterogeneous tumor subpopulations to metabolic inhibitors are poorly understood. Here, by using clinically-relevant patient-derived glioblastoma (GBM) cell models, we explore the cross-talk between glycolysis, autophagy, and senescence in maintaining tumor stemness. We found that stem cell-like GBM tumor subpopulations possessed higher basal levels of glycolytic activity and increased expression of several glycolysis-related enzymes including, GLUT1/SLC2A1, PFKP, ALDOA, GAPDH, ENO1, PKM2, and LDH, compared to their non-stem-like counterparts. Importantly, bioinformatics analysis also revealed that the mRNA expression of glycolytic enzymes positively correlates with stemness markers (CD133/PROM1 and SOX2) in patient GBM tumors. While treatment with glycolysis inhibitors induced senescence in stem cell-like GBM tumor subpopulations, as evidenced by increased β-galactosidase staining and upregulation of the cell cycle regulators p21Waf1/Cip1/CDKN1A and p16INK4A/CDKN2A, these cells maintained their aggressive stemness features and failed to undergo apoptotic cell death. Using various techniques including autophagy flux and EGFP-MAP1LC3B+ puncta formation analysis, we determined that inhibition of glycolysis led to the induction of autophagy in stem cell-like GBM tumor subpopulations, but not in their non-stem-like counterparts. Similarly, blocking autophagy in stem cell-like GBM tumor subpopulations induced senescence-associated growth arrest without hampering stemness capacity or inducing apoptosis while reciprocally upregulating glycolytic activity. Combinatorial treatment of stem cell-like GBM tumor subpopulations with autophagy and glycolysis inhibitors blocked the induction of senescence while drastically impairing their stemness capacity which drove cells towards apoptotic cell death. These findings identify a novel and complex compensatory interplay between glycolysis, autophagy, and senescence that helps maintain stemness in heterogeneous GBM tumor subpopulations and provides a survival advantage during metabolic stress.https://doi.org/10.1186/s40478-023-01604-yGlioblastomaTumor heterogeneityCancer stem cell-like cellsMetabolismGlycolysisAutophagy |
| spellingShingle | Emma Martell Helgi Kuzmychova Harshal Senthil Esha Kaul Chirayu R. Chokshi Chitra Venugopal Christopher M. Anderson Sheila K. Singh Tanveer Sharif Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations Acta Neuropathologica Communications Glioblastoma Tumor heterogeneity Cancer stem cell-like cells Metabolism Glycolysis Autophagy |
| title | Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations |
| title_full | Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations |
| title_fullStr | Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations |
| title_full_unstemmed | Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations |
| title_short | Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations |
| title_sort | compensatory cross talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations |
| topic | Glioblastoma Tumor heterogeneity Cancer stem cell-like cells Metabolism Glycolysis Autophagy |
| url | https://doi.org/10.1186/s40478-023-01604-y |
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