SFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance

Amanpreet Kaur, Marie R. Webster, Katie Marchbank, Reeti Behera, Abibatou Ndoye, Curtis H. Kugel, Vanessa M. Dang, Jessica Appleton, Michael P. O'Connell, Phil Cheng, Alexander A. Valiga, Rachel Morissette, Nazli B. McDonnell, Luigi Ferrucci, Andrew V. Kossenkov, Katrina Meeth, Hsin Yao Tang, Xiangfan Yin, William H. Wood, Elin LehrmannKevin G. Becker, Keith T. Flaherty, Dennie T. Frederick, Jennifer A. Wargo, Zachary A. Cooper, Michael T. Tetzlaff, Courtney Hudgens, Katherine M. Aird, Rugang Zhang, Xiaowei Xu, Qin Liu, Edmund Bartlett, Giorgos Karakousis, Zeynep Eroglu, Roger S. Lo, Matthew Chan, Alexander M. Menzies, Georgina V. Long, Douglas B. Johnson, Jeffrey Sosman, Bastian Schilling, Dirk Schadendorf, David W. Speicher, Marcus Bosenberg, Antoni Ribas, Ashani T. Weeraratna

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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.

Original languageEnglish (US)
Pages (from-to)250-254
Number of pages5
JournalNature
Volume532
Issue number7598
DOIs
StatePublished - Apr 14 2016

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Kaur, A., Webster, M. R., Marchbank, K., Behera, R., Ndoye, A., Kugel, C. H., Dang, V. M., Appleton, J., O'Connell, M. P., Cheng, P., Valiga, A. A., Morissette, R., McDonnell, N. B., Ferrucci, L., Kossenkov, A. V., Meeth, K., Tang, H. Y., Yin, X., Wood, W. H., ... Weeraratna, A. T. (2016). SFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature, 532(7598), 250-254. https://doi.org/10.1038/nature17392