A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity
Cancer metabolism plays an essential role in therapeutic resistance, where significant inter- and intra-tumoral heterogeneity exists. Hypoxia is a prominent driver of metabolic rewiring behaviors and drug responses. Recapitulating the hypoxic landscape in the tumor microenvironment thus offers uniqu...
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| Format: | Article |
| Language: | English |
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KeAi Communications Co., Ltd.
2025-06-01
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| Series: | Bioactive Materials |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X25000866 |
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| author | Jeong Min Oh Tianze Guo Hydari Masuma Begum Saci-Elodie Marty Liang Sha Cem Kilic Hao Zhou Yali Dou Keyue Shen |
| author_facet | Jeong Min Oh Tianze Guo Hydari Masuma Begum Saci-Elodie Marty Liang Sha Cem Kilic Hao Zhou Yali Dou Keyue Shen |
| author_sort | Jeong Min Oh |
| collection | DOAJ |
| description | Cancer metabolism plays an essential role in therapeutic resistance, where significant inter- and intra-tumoral heterogeneity exists. Hypoxia is a prominent driver of metabolic rewiring behaviors and drug responses. Recapitulating the hypoxic landscape in the tumor microenvironment thus offers unique insights into heterogeneity in metabolic rewiring and therapeutic responses, to inform better treatment strategies. There remains a lack of scalable tools that can readily interface with imaging platforms and resolve the heterogeneous behaviors in hypoxia-associated metabolic rewiring. Here we present a micro-metabolic rewiring (μMeRe) assay that provides the scalability and resolution needed to characterize the metabolic rewiring behaviors of different cancer cells in the context of hypoxic solid tumors. Our assay generates hypoxia through cellular metabolism without external gas controls, enabling the characterization of cell-specific intrinsic ability to drive hypoxia and undergo metabolic rewiring. We further developed quantitative metrics that measure the metabolic plasticity through phenotypes and gene expression. As a proof-of-concept, we evaluated the efficacy of a metabolism-targeting strategy in mitigating hypoxia- and metabolic rewiring-induced chemotherapeutic resistance. Our study and the scalable platform thus lay the foundation for designing more effective cancer treatments tailored toward specific metabolic rewiring behaviors. |
| format | Article |
| id | doaj-art-c856b68bb2b044748d47b4fa08e2abeb |
| institution | DOAJ |
| issn | 2452-199X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Bioactive Materials |
| spelling | doaj-art-c856b68bb2b044748d47b4fa08e2abeb2025-08-20T03:14:54ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2025-06-014849350910.1016/j.bioactmat.2025.02.030A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneityJeong Min Oh0Tianze Guo1Hydari Masuma Begum2Saci-Elodie Marty3Liang Sha4Cem Kilic5Hao Zhou6Yali Dou7Keyue Shen8Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USADepartment of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USADepartment of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USADepartment of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USADepartment of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USADepartment of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USADepartment of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USADepartment of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USADepartment of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA; USC Stem Cell, University of Southern California, Los Angeles, CA, 90033, USA; Corresponding author. Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USA.Cancer metabolism plays an essential role in therapeutic resistance, where significant inter- and intra-tumoral heterogeneity exists. Hypoxia is a prominent driver of metabolic rewiring behaviors and drug responses. Recapitulating the hypoxic landscape in the tumor microenvironment thus offers unique insights into heterogeneity in metabolic rewiring and therapeutic responses, to inform better treatment strategies. There remains a lack of scalable tools that can readily interface with imaging platforms and resolve the heterogeneous behaviors in hypoxia-associated metabolic rewiring. Here we present a micro-metabolic rewiring (μMeRe) assay that provides the scalability and resolution needed to characterize the metabolic rewiring behaviors of different cancer cells in the context of hypoxic solid tumors. Our assay generates hypoxia through cellular metabolism without external gas controls, enabling the characterization of cell-specific intrinsic ability to drive hypoxia and undergo metabolic rewiring. We further developed quantitative metrics that measure the metabolic plasticity through phenotypes and gene expression. As a proof-of-concept, we evaluated the efficacy of a metabolism-targeting strategy in mitigating hypoxia- and metabolic rewiring-induced chemotherapeutic resistance. Our study and the scalable platform thus lay the foundation for designing more effective cancer treatments tailored toward specific metabolic rewiring behaviors.http://www.sciencedirect.com/science/article/pii/S2452199X25000866Metabolic rewiringHypoxiaTumor heterogeneityMetabolism-targeting therapyTumor microenvironment |
| spellingShingle | Jeong Min Oh Tianze Guo Hydari Masuma Begum Saci-Elodie Marty Liang Sha Cem Kilic Hao Zhou Yali Dou Keyue Shen A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity Bioactive Materials Metabolic rewiring Hypoxia Tumor heterogeneity Metabolism-targeting therapy Tumor microenvironment |
| title | A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity |
| title_full | A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity |
| title_fullStr | A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity |
| title_full_unstemmed | A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity |
| title_short | A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity |
| title_sort | micro metabolic rewiring assay for assessing hypoxia associated cancer metabolic heterogeneity |
| topic | Metabolic rewiring Hypoxia Tumor heterogeneity Metabolism-targeting therapy Tumor microenvironment |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X25000866 |
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