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 Lehrmann; Kevin 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

doi:10.1038/nature17392

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

Research output: Contribution to journal › Article › peer-review

171 Scopus citations

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 language	English (US)
Pages (from-to)	250-254
Number of pages	5
Journal	Nature
Volume	532
Issue number	7598
DOIs	https://doi.org/10.1038/nature17392
State	Published - Apr 14 2016
Externally published	Yes

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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

Kaur, A, Webster, MR, Marchbank, K, Behera, R, Ndoye, A, Kugel, CH, Dang, VM, Appleton, J, O'Connell, MP, Cheng, P, Valiga, AA, Morissette, R, McDonnell, NB, Ferrucci, L, Kossenkov, AV, Meeth, K, Tang, HY, Yin, X, Wood, WH, Lehrmann, E, Becker, KG, Flaherty, KT, Frederick, DT, Wargo, JA, Cooper, ZA, Tetzlaff, MT, Hudgens, C, Aird, KM, Zhang, R, Xu, X, Liu, Q, Bartlett, E, Karakousis, G, Eroglu, Z, Lo, RS, Chan, M, Menzies, AM, Long, GV, Johnson, DB, Sosman, J, Schilling, B, Schadendorf, D, Speicher, DW, Bosenberg, M, Ribas, A & Weeraratna, AT 2016, 'SFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance', Nature, vol. 532, no. 7598, pp. 250-254. https://doi.org/10.1038/nature17392

@article{2f22a14633bc44cba0690b5695671bfe,

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 = "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",

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TY - JOUR

T1 - SFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance

AU - Kaur, Amanpreet

AU - Webster, Marie R.

AU - Marchbank, Katie

AU - Behera, Reeti

AU - Ndoye, Abibatou

AU - Kugel, Curtis H.

AU - Dang, Vanessa M.

AU - Appleton, Jessica

AU - O'Connell, Michael P.

AU - Cheng, Phil

AU - Valiga, Alexander A.

AU - Morissette, Rachel

AU - McDonnell, Nazli B.

AU - Ferrucci, Luigi

AU - Kossenkov, Andrew V.

AU - Meeth, Katrina

AU - Tang, Hsin Yao

AU - Yin, Xiangfan

AU - Wood, William H.

AU - Lehrmann, Elin

AU - Becker, Kevin G.

AU - Flaherty, Keith T.

AU - Frederick, Dennie T.

AU - Wargo, Jennifer A.

AU - Cooper, Zachary A.

AU - Tetzlaff, Michael T.

AU - Hudgens, Courtney

AU - Aird, Katherine M.

AU - Zhang, Rugang

AU - Xu, Xiaowei

AU - Liu, Qin

AU - Bartlett, Edmund

AU - Karakousis, Giorgos

AU - Eroglu, Zeynep

AU - Lo, Roger S.

AU - Chan, Matthew

AU - Menzies, Alexander M.

AU - Long, Georgina V.

AU - Johnson, Douglas B.

AU - Sosman, Jeffrey

AU - Schilling, Bastian

AU - Schadendorf, Dirk

AU - Speicher, David W.

AU - Bosenberg, Marcus

AU - Ribas, Antoni

AU - Weeraratna, Ashani T.

PY - 2016/4/14

Y1 - 2016/4/14

N2 - 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.

AB - 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.

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M3 - Article

C2 - 27042933

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SN - 0028-0836

VL - 532

SP - 250

EP - 254

JO - Nature

JF - Nature

IS - 7598

ER -

SFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance

Abstract

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