Multi-Omic Approaches Identify Metabolic and Autophagy Regulators Important in Ovarian Cancer Dissemination

Lindsay J Wheeler; Zachary L Watson; Lubna Qamar; Tomomi M Yamamoto; Brandon T Sawyer; Kelly D Sullivan; Santosh Khanal; Molishree Joshi; Veronique Ferchaud-Roucher; Harry Smith; Lauren A Vanderlinden; Sky W Brubaker; Cecilia M Caino; Hyunmin Kim; Joaquin M Espinosa; Jennifer K Richer; Benjamin G Bitler

doi:10.1016/j.isci.2019.07.049

Multi-Omic Approaches Identify Metabolic and Autophagy Regulators Important in Ovarian Cancer Dissemination

iScience. 2019 Sep 27:19:474-491. doi: 10.1016/j.isci.2019.07.049. Epub 2019 Aug 6.

Authors

Lindsay J Wheeler¹, Zachary L Watson², Lubna Qamar², Tomomi M Yamamoto², Brandon T Sawyer¹, Kelly D Sullivan³, Santosh Khanal³, Molishree Joshi³, Veronique Ferchaud-Roucher¹, Harry Smith⁴, Lauren A Vanderlinden⁴, Sky W Brubaker⁵, Cecilia M Caino⁶, Hyunmin Kim⁷, Joaquin M Espinosa³, Jennifer K Richer⁸, Benjamin G Bitler⁹

Affiliations

¹ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
² Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, 12700 E. 19(th) Avenue, MS 8613, Aurora, CO 80045, USA.
³ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, CO 80045, USA.
⁴ Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁵ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
⁷ Translational Bioinformatics and Cancer Systems Biology Laboratory, Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁸ Department of Pathology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
⁹ Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, 12700 E. 19(th) Avenue, MS 8613, Aurora, CO 80045, USA. Electronic address: benjamin.bitler@ucdenver.edu.

Abstract

High-grade serous ovarian cancers (HGSOCs) arise from exfoliation of transformed cells from the fallopian tube, indicating that survival in suspension, and potentially escape from anoikis, is required for dissemination. We report here the results of a multi-omic study to identify drivers of anoikis escape, including transcriptomic analysis, global non-targeted metabolomics, and a genome-wide CRISPR/Cas9 knockout (GeCKO) screen of HGSOC cells cultured in adherent and suspension settings. Our combined approach identified known pathways, including NOTCH signaling, as well as novel regulators of anoikis escape. Newly identified genes include effectors of fatty acid metabolism, ACADVL and ECHDC2, and an autophagy regulator, ULK1. Knockdown of these genes significantly inhibited suspension growth of HGSOC cells, and the metabolic profile confirmed the role of fatty acid metabolism in survival in suspension. Integration of our datasets identified an anoikis-escape gene signature that predicts overall survival in many carcinomas.

Keywords: Biological Sciences; Cancer; Cancer Systems Biology; Cell Biology.

Abstract

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