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.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.|University of the Sciences, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Amanpreet
authors.initials: A
authors.lastname: Kaur
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Marie R
authors.initials: MR
authors.lastname: Webster
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Marchbank
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Reeti
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authors.lastname: Behera
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Abibatou
authors.initials: A
authors.lastname: Ndoye
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Curtis H
authors.initials: CH
authors.lastname: Kugel
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Dang
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jessica
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authors.lastname: Appleton
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: O'Connell
authors.affiliation: Department of Dermatology, University of Zurich, Zurich CH-8006, Switzerland.
authors.forename: Phil
authors.initials: P
authors.lastname: Cheng
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Valiga
authors.affiliation: The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Morissette
authors.affiliation: The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Nazli B
authors.initials: NB
authors.lastname: McDonnell
authors.affiliation: The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.affiliation: Department of Dermatology and Pathology, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Katrina
authors.initials: K
authors.lastname: Meeth
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Hsin-Yao
authors.initials: HY
authors.lastname: Tang
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Xiangfan
authors.initials: X
authors.lastname: Yin
authors.affiliation: The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Wood
authors.affiliation: The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Elin
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authors.lastname: Lehrmann
authors.affiliation: The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.affiliation: Massachusetts General Hospital Cancer Center, Developmental Therapeutics, Boston 02114, Massachusetts, USA.
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authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Massachusetts General Hospital Cancer Center, Developmental Therapeutics, Boston 02114, Massachusetts, USA.
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.affiliation: Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tetzlaff
authors.affiliation: Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Hudgens
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Aird
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Departments of Surgery and Pathology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Departments of Surgery and Pathology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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authors.initials: E
authors.lastname: Bartlett
authors.affiliation: Departments of Surgery and Pathology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Giorgos
authors.initials: G
authors.lastname: Karakousis
authors.affiliation: Department of Medical Oncology, City of Hope Medical Center, Duarte, California 91010, USA.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Eroglu
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
authors.affiliation: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead 2145, Australia.
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authors.lastname: Chan
authors.affiliation: Melanoma Institute Australia and The University of Sydney, Sydney 2000, Australia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: Melanoma Institute Australia and The University of Sydney, Sydney 2000, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville Tennessee 37232, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville Tennessee 37232, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sosman
authors.affiliation: Department of Dermatology, University Hospital, West German Cancer Center, University Duesburg-Essen, Essen, Germany.|German Cancer Consortium (DKTK), Heidelberg 45127, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Schilling
authors.affiliation: Department of Dermatology, University Hospital, West German Cancer Center, University Duesburg-Essen, Essen, Germany.|German Cancer Consortium (DKTK), Heidelberg 45127, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Speicher
authors.affiliation: Department of Dermatology and Pathology, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ashani T
authors.initials: AT
authors.lastname: Weeraratna
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004249:DNA Damage; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D018384:Oxidative Stress; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D059016:Tumor Microenvironment; D000077484:Vemurafenib; D060449:Wnt Signaling Pathway; D051155:Wnt1 Protein / Q000037:antagonists & inhibitors; D051176:beta Catenin / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D017077:Culture Media, Conditioned; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D007211:Indoles; D008565:Membrane Proteins; D051739:Microphthalmia-Associated Transcription Factor; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D000077484:Vemurafenib; D051155:Wnt1 Protein; D051176:beta Catenin; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C085108:APEX1 protein, human