TY - JOUR
T1 - Stromal changes in the aged lung induce an emergence from melanoma dormancy
AU - Fane, Mitchell E.
AU - Chhabra, Yash
AU - Alicea, Gretchen M.
AU - Maranto, Devon A.
AU - Douglass, Stephen M.
AU - Webster, Marie R.
AU - Rebecca, Vito W.
AU - Marino, Gloria E.
AU - Almeida, Filipe
AU - Ecker, Brett L.
AU - Zabransky, Daniel J.
AU - Hüser, Laura
AU - Beer, Thomas
AU - Tang, Hsin Yao
AU - Kossenkov, Andrew
AU - Herlyn, Meenhard
AU - Speicher, David W.
AU - Xu, Wei
AU - Xu, Xiaowei
AU - Jaffee, Elizabeth M.
AU - Aguirre-Ghiso, Julio A.
AU - Weeraratna, Ashani T.
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/6/9
Y1 - 2022/6/9
N2 - 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.
AB - 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.
KW - Aged
KW - Aging/pathology
KW - Axl Receptor Tyrosine Kinase
KW - Fibroblasts/pathology
KW - Humans
KW - Lung/pathology
KW - Melanoma/pathology
KW - Neoplasm Invasiveness/pathology
KW - Neoplasm Metastasis/pathology
KW - Neoplasm, Residual
KW - Proto-Oncogene Proteins
KW - Receptor Protein-Tyrosine Kinases
KW - Skin/pathology
KW - Stromal Cells/pathology
KW - Tumor Microenvironment
KW - Wnt-5a Protein
KW - c-Mer Tyrosine Kinase
UR - http://www.scopus.com/inward/record.url?scp=85131315752&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000804522000006&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1038/s41586-022-04774-2
DO - 10.1038/s41586-022-04774-2
M3 - Article
C2 - 35650435
SN - 0028-0836
VL - 606
SP - 396
EP - 405
JO - Nature
JF - Nature
IS - 7913
ER -