Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression1,2,3,4, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in β-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.
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Gene Expression Omnibus
Microarray data are available in the GEO database under accession number GSE57445.
We thank D. Altieri, R. Marais, Z. Ronai, M. McMahon, and B. Vogelstein for comments on the manuscript. We thank R. Somasundaram for advice on immune analyses, M. Herlyn for the WM cell lines, and G. Bollag for PLX4720. We also thank R. Delgiacco, D. Gourevitch, F. Keeney, and D. Schultz. We thank A. Dias-Wanigasekera, E. Gaddy, and M. Ha for technical assistance, and R. Locke for editing the manuscript. This work was supported in part by funds from the Intramural Program of the National Institute on Aging, Baltimore, Maryland (N.M., K.G.B., R.M., W.H.W., L.F.), The Harry J. Lloyd Foundation (K.M., A.T.W.), P01 CA 114046-06 (A.T.W., Q.L.), T32 CA 9171-36 (M.R.W., C.H.K.), an ACS-IRG award (A.T.W.), the Melanoma Research Foundation (A.T.W.), and RO1 CA174746-01 (A.T.W., A.K.). Core facilities at the Wistar are supported by Cancer Center Support Grant P30 CA010815.
Extended data figures
Extended data tables
This file contains the raw data for Figures 2a, 2g, 3a, 3e, 4f, 4g, 5b and Extended Data Figures 6b, 6c, 8e, 10b, 10c.
This file is a compilation of tables outlining the antibodies, vectors and primers used, and the sources from which they came. Extended statistics for patient data, as well as patient information are also included.
About this article
WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial–mesenchymal transition
Journal of Biological Chemistry (2019)