Stromal changes in the aged lung induce an emergence from melanoma dormancy

Mitchell E. Fane, Yash Chhabra, Gretchen M. Alicea, Devon A. Maranto, Stephen M. Douglass, Marie R. Webster, Vito W. Rebecca, Gloria E. Marino, Filipe Almeida, Brett L. Ecker, Daniel J. Zabransky, Laura Hüser, Thomas Beer, Hsin-Yao Tang, Andrew Kossenkov, Meenhard Herlyn, David W. Speicher, Wei Xu, Xiaowei Xu, Elizabeth M. Jaffee, Julio A. Aguirre-Ghiso and Ashani T. Weeraratna ()
Additional contact information
Mitchell E. Fane: Johns Hopkins Bloomberg School of Public Health
Yash Chhabra: Johns Hopkins Bloomberg School of Public Health
Gretchen M. Alicea: Johns Hopkins Bloomberg School of Public Health
Devon A. Maranto: Johns Hopkins School of Medicine
Stephen M. Douglass: Johns Hopkins Bloomberg School of Public Health
Marie R. Webster: Lankenau Institute for Medical Research
Vito W. Rebecca: Johns Hopkins Bloomberg School of Public Health
Gloria E. Marino: Johns Hopkins Bloomberg School of Public Health
Filipe Almeida: The Wistar Institute
Brett L. Ecker: The Wistar Institute
Daniel J. Zabransky: Johns Hopkins Bloomberg School of Public Health
Laura Hüser: Johns Hopkins Bloomberg School of Public Health
Thomas Beer: The Wistar Institute
Hsin-Yao Tang: The Wistar Institute
Andrew Kossenkov: The Wistar Institute
Meenhard Herlyn: The Wistar Institute
David W. Speicher: The Wistar Institute
Wei Xu: University of Pennsylvania
Xiaowei Xu: University of Pennsylvania
Elizabeth M. Jaffee: Johns Hopkins School of Medicine
Julio A. Aguirre-Ghiso: Albert Einstein College of Medicine
Ashani T. Weeraratna: Johns Hopkins Bloomberg School of Public Health

Nature, 2022, vol. 606, issue 7913, 396-405

Abstract: Abstract Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells—in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1–3. It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing4–8. We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-022-04774-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:606:y:2022:i:7913:d:10.1038_s41586-022-04774-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-04774-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().