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Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia

ABSTRACT: In tumor tissues, hypoxia is a commonly observed feature resulting from rapidly proliferating cancer cells outgrowing the surrounding vasculature network. The four-step isogenic BJ cell model enables studies of defined steps of tumorigenesis: the normal, immortalized, transformed, and metastasizing stages. By transcriptome profiling under atmospheric and moderate hypoxic (3% O2) conditions, we observed that despite being highly similar, the four cell lines responded strikingly different to hypoxia. We demonstrate that the transcriptome adaptation to moderate hypoxia resembles the process of malignant transformation. The transformed cells displayed a distinct capability of metabolic switching, reflected in reversed gene expression patterns for several genes involved in oxidative phosphorylation and glycolytic pathways. By profiling the stage-specific responses to hypoxia, we identified ASS1 as a potential prognostic marker in hypoxic tumors. This study demonstrates the usefulness of the BJ cell model for highlighting the interconnection of pathways involved in malignant transformation and hypoxic response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109367 | GEO | 2018/05/09

REPOSITORIES: GEO

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Project description:Tumor hypoxia is linked to poor outcome for many cancers, but the underlying mechanisms and the environmental factors that initiate tumor hypoxia are poorly understood. Here, we tracked tumor hypoxia in glioblastoma (GBM), a highly malignant brain cancer, in immunocompetent mice with a sensitive fluorescent reporter combined with single cell transcriptomics. We found that hypoxic GBM cells are quiescent and display a mesenchymal transition, both linked to malignant potency. We also captured in vivo hypoxia gene signature, which is more represented in recurrent GBM and predicts worse outcome. Interestingly, hypoxic GBM cells is a diverse population, consisted of four subclusters, and enriched for immune pathways. Concordantly, our reporter highlighted a distinct geographic pattern of immune cells in hypoxic regions, with phagocytic tumor-associated macrophages (TAMs) and CD8+ cytotoxic T cells (CTLs) congregated in hypoxic cores confined by hypoxic GBM cells in pseudopalisading patterns. Mechanistically, this is a dynamic temporospatial process, requiring cytokine CCL8. Remarkably, the sequestered TAMs also experience hypoxia, and they are reprogrammed to an immunotolerant state by factors released from hypoxic GBM cells. Contrary to the conventional viewpoint that hypoxia arises from rapid tumor expansion outstripping vascular supply, we discovered anticancer immunity as an important driving force of tumor hypoxia. Attenuating immune responses by implanting GBM in host mice with immunodeficiency or IL1β deletion significantly decreased GBM hypoxia in well-established tumors. Unexpectedly, radiation therapy (XRT) greatly reduced tumor hypoxia, and when combined with evofosfamide, a prodrug activated by hypoxia, achieved enhanced efficacy in tumor shrinkage and eradication of hypoxic GBM population. Analyses of human patient GBM samples highlighted a connection of mesenchymal subtype, immune response, and tumor hypoxia, all contributing to poor survival. Altogether, our study revealed a reciprocal influence of anti-tumor immunity and tumor hypoxia, which has important ramification for prognosis and immunotherapy for GBM.

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Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia

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