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Temporal multi-omic profiling reveals chemoradiotherapy-specific dualistic metabolic rewiring that supports glioblastoma tumor recurrence

ABSTRACT: Temporal multi-omic profiling reveals chemoradiotherapy-specific dualistic metabolic rewiring that supports glioblastoma tumor recurrence

PROVIDER: PRJNA1066399 | ENA |

REPOSITORIES: ENA

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Temporal multi-omic profiling reveals chemoradiotherapy-specific dualistic metabolic rewiring that supports glioblastoma tumor recurrence (scRNA-Seq)

Project description:Tumor recurrence afflicts over 95% of glioblastoma (GBM) patients, contributing to the disease's high fatality rates. To unravel the molecular mechanisms behind post-therapy recurrence, we employed a clinically-relevant chemoradiotherapy model, studying the temporal molecular metabolic evolution of patient-derived GBM samples in vitro and in vivo. Leveraging unbiased multi-omics methods, including single-cell and bulk transcriptomics, untargeted metabolomics, and stable isotope tracing, we revealed a dynamic metabolic rewiring favoring one-way anaplerotic pyruvate metabolism via carboxylation across GBM samples. This conserved adaptation, confirmed in independent datasets, resulted in reduced glucose-derived acetyl-coA production, hindering histone acetylation and silencing neural-differentiation genes NEUROD1 and DCX. Pharmacological intervention targeting this metabolic shift reduced recurrent GBM cell aggressiveness, prolonging survival in preclinical GBM xenograft tumors treated with chemoradiotherapy. These findings illuminate a potential metabolic therapeutic avenue to enhance current strategies, addressing disease recurrence and offering much-needed improvements in survival outcomes for GBM patients suffering from this dismal disease.

2025-07-02 | GSE253648 | GEO

Temporal multi-omic profiling reveals chemoradiotherapy-specific dualistic metabolic rewiring that supports glioblastoma tumor recurrence (Bulk RNA-Seq)

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Temporal multi-omic profiling reveals chemoradiotherapy-specific dualistic metabolic rewiring that supports glioblastoma tumor recurrence (scRNA-Seq)

Project description:Temporal multi-omic profiling reveals chemoradiotherapy-specific dualistic metabolic rewiring that supports glioblastoma tumor recurrence (scRNA-Seq)

| PRJNA1066401 | ENA

Temporal multi-omic profiling reveals chemoradiotherapy-specific dualistic metabolic rewiring that supports glioblastoma tumor recurrence (Bulk RNA-Seq)

Project description:Temporal multi-omic profiling reveals chemoradiotherapy-specific dualistic metabolic rewiring that supports glioblastoma tumor recurrence (Bulk RNA-Seq)

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Temporal multi-omic profiling reveals chemoradiotherapy-specific dualistic metabolic rewiring that supports glioblastoma tumor recurrence

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-07-02 | GSE253649 | GEO

Chemoradiotherapy-induced ACKR2+ tumor cells drive CD8+ T cell senescence and tumor recurrence

Project description:Chemoradiotherapy-induced ACKR2+ tumor cells drive CD8+ T cell senescence and tumor recurrence

| PRJNA992114 | ENA

Chemoradiotherapy-induced ACKR2+ tumor cells drive CD8+ T cell senescence and tumor recurrence

Project description:T cell senescence is a dysfunctional state distinct from exhaustion, yet the mechanism driving CD8+ T cell senescence directly in tumor microenvironment and its impact on cancer prognosis remain elusive. Here, by using single cell RNA sequencing of human cervical cancer tissues, we found that concurrent chemoradiotherapy (CCRT) specifically promoted CD8+ T cell senescence, which is driven by a subpopulation of ACKR2+ CCRT-resistance tumor cells. Mechanistically, in response to CCRT treatment, ACKR2 was directly induced and could also be upregulated through its ligands CC chemokines that produced by activated myeloid and T cells. Subsequently, these ACKR2+ tumor cell subpopulation also produced TGFβ to drive CD8+ T cell senescence, thereby compromising antitumor immunity. Moreover, retrospective analysis showed that ACKR2 level and CD8+ T cell senescence was greatly enhanced in cervical cancer patients who recurred after CCRT, thereby predicting poor prognosis in these patients. Overall, we identified a subpopulation of CCRT-resistant ACKR2+ tumor cells in driving CD8+ T cell senescence and thus tumor recurrence, which may represent a critical mechanism in mediating CCRT resistance, and highlighted the therapeutic potential of targeting ACKR2 or CD8+ T cell senescence in the treatment of CCRT-resistant cancer patients.

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