Characterization of hypoxia-associated molecular features to aid hypoxia-targeted therapy

Youqiong Ye, Qingsong Hu, Hu Chen, Ke Liang, Yuan Yuan, Yu Xiang, Hang Ruan, Zhao Zhang, Anren Song, Huiwen Zhang, Lingxiang Liu, Lixia Diao, Yanyan Lou, Bingying Zhou, Li Wang, Shengtao Zhou, Jianjun Gao, Eric Jonasch, Steven H. Lin, Yang XiaChunru Lin, Liuqing Yang, Gordon B. Mills, Han Liang, Leng Han

    Research output: Contribution to journalArticle

    9 Scopus citations

    Abstract

    Tumour hypoxia is a major contributor to resistance to anticancer therapies. Given that the results of hypoxia-targeted therapy trials have been disappointing, a more personalized approach may be needed. Here, we characterize multi-omic molecular features associated with tumour hypoxia and identify molecular alterations that correlate with both drug-resistant and drug-sensitive responses to anticancer drugs. Based on a well-established hypoxia gene expression signature, we classify about 10,000 tumour samples into hypoxia score-high and score-low groups across different cancer types from The Cancer Genome Atlas (TCGA) and demonstrate their prognostic associations. Then, we identify various types of molecular features associated with hypoxia status that correlate with drug resistance but, in some cases, also with drug sensitivity, contrasting the conventional view that hypoxia confers drug resistance. We further show that 110 out of 121 (90.9%) clinically actionable genes can be affected by hypoxia status and experimentally validate the predicted effects of hypoxia on the response to several drugs in cultured cells. Our study provides a comprehensive molecular-level understanding of tumour hypoxia and may have practical implications for clinical cancer therapy.

    Original languageEnglish (US)
    Pages (from-to)431-444
    Number of pages14
    JournalNature Metabolism
    Volume1
    Issue number4
    DOIs
    StatePublished - Apr 1 2019

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    ASJC Scopus subject areas

    • Endocrinology, Diabetes and Metabolism
    • Physiology (medical)
    • Internal Medicine
    • Cell Biology

    Cite this

    Ye, Y., Hu, Q., Chen, H., Liang, K., Yuan, Y., Xiang, Y., Ruan, H., Zhang, Z., Song, A., Zhang, H., Liu, L., Diao, L., Lou, Y., Zhou, B., Wang, L., Zhou, S., Gao, J., Jonasch, E., Lin, S. H., ... Han, L. (2019). Characterization of hypoxia-associated molecular features to aid hypoxia-targeted therapy. Nature Metabolism, 1(4), 431-444. https://doi.org/10.1038/s42255-019-0045-8