Development of adaptive anoikis resistance promotes metastasis that can be overcome by CDK8/19 Mediator kinase inhibition.

Autor:	Monavarian M; Division of Molecular Cellular Pathology, Department of Pathology, O'Neal Comprehensive Cancer Center, University of Alabama, Heersink School of Medicine, Birmingham, AL, USA., Page EF; Division of Molecular Cellular Pathology, Department of Pathology, O'Neal Comprehensive Cancer Center, University of Alabama, Heersink School of Medicine, Birmingham, AL, USA., Rajkarnikar R; Division of Molecular Cellular Pathology, Department of Pathology, O'Neal Comprehensive Cancer Center, University of Alabama, Heersink School of Medicine, Birmingham, AL, USA., Kumari A; Division of Molecular Cellular Pathology, Department of Pathology, O'Neal Comprehensive Cancer Center, University of Alabama, Heersink School of Medicine, Birmingham, AL, USA., Macias LQ; Division of Molecular Cellular Pathology, Department of Pathology, O'Neal Comprehensive Cancer Center, University of Alabama, Heersink School of Medicine, Birmingham, AL, USA., Massicano F; UAB Biological Data Science Core, The University of Alabama at Birmingham, Birmingham, Alabama, USA., Lee NY; Division of Pharmacology, Chemistry and Biochemistry, College of Medicine, University of Arizona, Tucson, AZ, 85721, USA., Sahoo S; Department of Bioengineering, Indian Institute of Science, Bangalore, 560012, India., Hempel N; Department of Medicine, Division of Hematology Oncology, University of Pittsburgh School of Medicine Pittsburgh PA 15213., Jolly MK; Department of Bioengineering, Indian Institute of Science, Bangalore, 560012, India., Ianov L; UAB Biological Data Science Core, The University of Alabama at Birmingham, Birmingham, Alabama, USA.; Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, Alabama, USA., Worthey E; UAB Biological Data Science Core, The University of Alabama at Birmingham, Birmingham, Alabama, USA., Singh A; Department of Electrical and Computer Engineering, University of Delaware, Newark, DE 19716, USA., Broude EV; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA., Mythreye K; Division of Molecular Cellular Pathology, Department of Pathology, O'Neal Comprehensive Cancer Center, University of Alabama, Heersink School of Medicine, Birmingham, AL, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 06. Date of Electronic Publication: 2023 Dec 06.
DOI:	10.1101/2023.12.04.569970
Abstrakt:	Anoikis resistance or evasion of cell death triggered by cell detachment into suspension is a hallmark of cancer that is concurrent with cell survival and metastasis. The effects of frequent matrix detachment encounters on the development of anoikis resistance in cancer remains poorly defined. Here we show using a panel of ovarian cancer models, that repeated exposure to suspension stress in vitro followed by attached recovery growth leads to the development of anoikis resistance paralleling in vivo development of anoikis resistance in ovarian cancer ascites. This resistance is concurrent with enhanced invasion, chemoresistance and the ability of anoikis adapted cells to metastasize to distant sites. Adapted anoikis resistant cells show a heightened dependency on oxidative phosphorylation and can also evade immune surveillance. We find that such acquired anoikis resistance is not genetic, as acquired resistance persists for a finite duration in the absence of suspension stress. Transcriptional reprogramming is however essential to this process, as acquisition of adaptive anoikis resistance in vitro and in vivo is exquisitely sensitive to inhibition of CDK8/19 Mediator kinase, a pleiotropic regulator of transcriptional reprogramming. Our data demonstrate that growth after recovery from repeated exposure to suspension stress is a direct contributor to metastasis and that inhibition of CDK8/19 Mediator kinase during such adaptation provides a therapeutic opportunity to prevent both local and distant metastasis in cancer. Competing Interests: Conflict of interest statement : E.V.B. is a consultant of Senex Biotechnology, Inc
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu