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.Reca-...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.Reca-pitulating 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 meta-bolic rewiring.We further developed quantitative metrics that measure the metabolic plasticity through phe-notypes 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 meta-bolic rewiring behaviors.展开更多
基金supported by the USC Graduate School Provost Fellowship,USC Viterbi School of Engineering,a National Institutes of Health(NIH)grant R01CA220012,and a STOP CANCER Marni Levine Memorial Research Career Development Awardsupported by shared resources from an NIH National Cancer Institute Award(P30CA014089).
文摘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.Reca-pitulating 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 meta-bolic rewiring.We further developed quantitative metrics that measure the metabolic plasticity through phe-notypes 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 meta-bolic rewiring behaviors.
