Unchecked oxidative stress in skeletal muscle prevents outgrowth of disseminated tumour cells.

Autor: Crist SB; Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.; Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, WA, USA., Nemkov T; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Dumpit RF; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Dai J; Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Tapscott SJ; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.; Department of Neurology, University of Washington, Seattle, WA, USA., True LD; Department of Urology, University of Washington, Seattle, WA, USA.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Swarbrick A; The Kinghorn Cancer Centre and Cancer Research Theme, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia., Sullivan LB; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Nelson PS; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.; Department of Urology, University of Washington, Seattle, WA, USA.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.; Department of Medicine, University of Washington, Seattle, WA, USA., Hansen KC; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Ghajar CM; Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. cghajar@fredhutch.org.; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. cghajar@fredhutch.org.
Jazyk: angličtina
Zdroj: Nature cell biology [Nat Cell Biol] 2022 Apr; Vol. 24 (4), pp. 538-553. Date of Electronic Publication: 2022 Apr 11.
DOI: 10.1038/s41556-022-00881-4
Abstrakt: Skeletal muscle has long been recognized as an inhospitable site for disseminated tumour cells (DTCs). Yet its antimetastatic nature has eluded a thorough mechanistic examination. Here, we show that DTCs traffic to and persist within skeletal muscle in mice and in humans, which raises the question of how this tissue suppresses colonization. Results from mouse and organotypic culture models along with metabolomic profiling suggested that skeletal muscle imposes a sustained oxidative stress on DTCs that impairs their proliferation. Functional studies demonstrated that disrupting reduction-oxidation homeostasis via chemogenetic induction of reactive oxygen species slowed proliferation in a more fertile organ: the lung. Conversely, enhancement of the antioxidant potential of tumour cells through ectopic expression of catalase in the tumour or host mitochondria allowed robust colonization of skeletal muscle. These findings reveal a profound metabolic bottleneck imposed on DTCs and sustained by skeletal muscle. A thorough understanding of this biology could reveal previously undocumented DTC vulnerabilities that can be exploited to prevent metastasis in other more susceptible tissues.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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