@article{11e3dbb37a954963803799c4aaf4c747,
title = "SFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance",
abstract = "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 progression, 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.",
author = "Amanpreet Kaur and Webster, {Marie R.} and Katie Marchbank and Reeti Behera and Abibatou Ndoye and Kugel, {Curtis H.} and Dang, {Vanessa M.} and Jessica Appleton and O'Connell, {Michael P.} and Phil Cheng and Valiga, {Alexander A.} and Rachel Morissette and McDonnell, {Nazli B.} and Luigi Ferrucci and Kossenkov, {Andrew V.} and Katrina Meeth and Tang, {Hsin Yao} and Xiangfan Yin and Wood, {William H.} and Elin Lehrmann and Becker, {Kevin G.} and Flaherty, {Keith T.} and Frederick, {Dennie T.} and Wargo, {Jennifer A.} and Cooper, {Zachary A.} and Tetzlaff, {Michael T.} and Courtney Hudgens and Aird, {Katherine M.} and Rugang Zhang and Xiaowei Xu and Qin Liu and Edmund Bartlett and Giorgos Karakousis and Zeynep Eroglu and Lo, {Roger S.} and Matthew Chan and Menzies, {Alexander M.} and Long, {Georgina V.} and Johnson, {Douglas B.} and Jeffrey Sosman and Bastian Schilling and Dirk Schadendorf and Speicher, {David W.} and Marcus Bosenberg and Antoni Ribas and Weeraratna, {Ashani T.}",
note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited.",
year = "2016",
month = apr,
day = "14",
doi = "10.1038/nature17392",
language = "English (US)",
volume = "532",
pages = "250--254",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7598",
}