机构：[1]Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston,TX, USA[2]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[3]Department ofBioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[4]Graduate Program in Quantitativeand Computational Biosciences, Baylor College of Medicine, Houston, TX, USA[5]Department of Oncology, The First Affiliated Hospital of NanjingMedical University, Nanjing, China内科系统肿瘤科江苏省人民医院[6]Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA[7]State Key Laboratory of CardiovascularDisease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing,China[8]Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State KeyLaboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China[9]Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[10]Department of RadiationOncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[11]MD Anderson Cancer CenterUTHealth Graduate School of Biomedical Sciences, Houston, TX, USA[12]Department of Systems Biology, The University of Texas MD AndersonCancer Center, Houston, TX, USA[13]Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA[14]Center for Precision Health,The University of Texas Health Science Center at Houston, Houston, TX, USA
Tumor hypoxia is a major contributor to resistance to anti-cancer 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 tumor hypoxia and identify molecular alterations that correlate with both drug-resistant and drug-sensitive responses to anti-cancer drugs. Based on a well-established hypoxia gene expression signature, we classify about 10,000 tumor samples into hypoxia score-high and score-low groups across different cancer types from The Cancer Genome Atlas and demonstrate their prognostic associations. We then 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 tumor hypoxia and may have practical implications for clinical cancer therapy.
基金：
Cancer Prevention & Research Institute of Texas
(grant no. RR150085 to L.H., grant no. RP140462 to H.L., grant nos. RP150094 and
RP180259 to C.L. and grant no. R1218 to L.Y.); the National Institutes of Health (grant nos. CA168394, CA098258 and CA143883 to G.B.M., grant no. CA175486 to H.L.,
grant no. CA209851 to H.L. and G.B.M., grant no. R00DK094981, 1R01CA218025 and
1R01CA231011 to C.L., grant no. R00CA166527 and 1R01CA218036 to L.Y. and grant
no. R01 HL137990 and 1R01HL136969 to Y.X.). Department of Defense Breakthrough
Awards were granted to C.L. and L.Y. (award no. BC180196 to C.L. and award
no. BC151465 to L.Y.). The American Association for Cancer Research–Bayer Innovation
and Discovery Grant (no. 18-80-44) and Andrew Sabin Family Foundation Fellows
Award were awarded to L.Y., J.G. was awarded an MD Anderson Physician Scientist
Award, a Khalifa Physician Scientist Award, an Andrew Sabin Family Foundation
Fellows Award, an MD Anderson Faculty Scholar Award and a Doris Duke Charitable
Foundation Career Development Award (award no. 2018097). The National Natural
Science Foundation of China supported S.Z. with grant nos. 81822034 and 81773119.
We gratefully acknowledge contributions from the TCGA Research Network. We thank
L.-A. Chastain for editorial assistance.
第一作者机构：[1]Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston,TX, USA
共同第一作者：
通讯作者：
通讯机构：[1]Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston,TX, USA[2]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[3]Department ofBioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[4]Graduate Program in Quantitativeand Computational Biosciences, Baylor College of Medicine, Houston, TX, USA[11]MD Anderson Cancer CenterUTHealth Graduate School of Biomedical Sciences, Houston, TX, USA[12]Department of Systems Biology, The University of Texas MD AndersonCancer Center, Houston, TX, USA[13]Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA[14]Center for Precision Health,The University of Texas Health Science Center at Houston, Houston, TX, USA
推荐引用方式(GB/T 7714)：
Ye Youqiong,Hu Qingsong,Chen Hu,et al.Characterization of Hypoxia-associated Molecular Features to Aid Hypoxia-Targeted Therapy.[J].NATURE METABOLISM.2019,1(4):431-444.doi:10.1038/s42255-019-0045-8.
APA：
Ye Youqiong,Hu Qingsong,Chen Hu,Liang Ke,Yuan Yuan...&Han Leng.(2019).Characterization of Hypoxia-associated Molecular Features to Aid Hypoxia-Targeted Therapy..NATURE METABOLISM,1,(4)
MLA：
Ye Youqiong,et al."Characterization of Hypoxia-associated Molecular Features to Aid Hypoxia-Targeted Therapy.".NATURE METABOLISM 1..4(2019):431-444
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