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
Affiliations
Lindsay J. Wheeler
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO 80045, USA
Zachary L. Watson
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, 12700 E. 19th Avenue, MS 8613, Aurora, CO 80045, USA
Lubna Qamar
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, 12700 E. 19th Avenue, MS 8613, Aurora, CO 80045, USA
Tomomi M. Yamamoto
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, 12700 E. 19th Avenue, MS 8613, Aurora, CO 80045, USA
Brandon T. Sawyer
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO 80045, USA
Kelly D. Sullivan
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
Santosh Khanal
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
Molishree Joshi
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
Veronique Ferchaud-Roucher
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO 80045, USA
Harry Smith
Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Lauren A. Vanderlinden
Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Sky W. Brubaker
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
Cecilia M. Caino
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
Hyunmin Kim
Translational Bioinformatics and Cancer Systems Biology Laboratory, Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Joaquin M. Espinosa
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
Jennifer K. Richer
Department of Pathology, University of Colorado School of Medicine, Aurora, CO 80045, USA
Benjamin G. Bitler
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, 12700 E. 19th Avenue, MS 8613, Aurora, CO 80045, USA; Corresponding author
Summary: 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. : Biological Sciences; Cell Biology; Cancer Systems Biology; Cancer Subject Areas: Biological Sciences, Cell Biology, Cancer Systems Biology, Cancer
