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sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance.

  • Kaur A The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Webster MR The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Marchbank K The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Behera R The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Ndoye A The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Kugel CH The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Dang VM The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Appleton J The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • O'Connell MP The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Cheng P Department of Dermatology, University of Zurich, Zurich CH-8006, Switzerland.
  • Valiga AA The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Morissette R The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
  • McDonnell NB The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
  • Ferrucci L The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
  • Kossenkov AV The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Meeth K Department of Dermatology and Pathology, Yale University, New Haven, Connecticut 06511, USA.
  • Tang HY The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Yin X The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Wood WH The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
  • Lehrmann E The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
  • Becker KG The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
  • Flaherty KT Massachusetts General Hospital Cancer Center, Developmental Therapeutics, Boston 02114, Massachusetts, USA.
  • Frederick DT Massachusetts General Hospital Cancer Center, Developmental Therapeutics, Boston 02114, Massachusetts, USA.
  • Wargo JA Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • Cooper ZA Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • Tetzlaff MT Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • Hudgens C Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • Aird KM The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Zhang R The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Xu X Departments of Surgery and Pathology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • Liu Q The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Bartlett E Departments of Surgery and Pathology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • Karakousis G Departments of Surgery and Pathology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • Eroglu Z Department of Medical Oncology, City of Hope Medical Center, Duarte, California 91010, USA.
  • Lo RS Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Chan M Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead 2145, Australia.
  • Menzies AM Melanoma Institute Australia and The University of Sydney, Sydney 2000, Australia.
  • Long GV Melanoma Institute Australia and The University of Sydney, Sydney 2000, Australia.
  • Johnson DB Department of Medicine, Vanderbilt University Medical Center, Nashville Tennessee 37232, USA.
  • Sosman J Department of Medicine, Vanderbilt University Medical Center, Nashville Tennessee 37232, USA.
  • Schilling B Department of Dermatology, University Hospital, West German Cancer Center, University Duesburg-Essen, Essen, Germany.
  • Schadendorf D Department of Dermatology, University Hospital, West German Cancer Center, University Duesburg-Essen, Essen, Germany.
  • Speicher DW The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Bosenberg M Department of Dermatology and Pathology, Yale University, New Haven, Connecticut 06511, USA.
  • Ribas A Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Weeraratna AT The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
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  • 2016-04-05
Published in:
  • Nature. - 2016
Adult
Aging
Animals
Cell Line, Tumor
Culture Media, Conditioned
DNA Damage
DNA-(Apurinic or Apyrimidinic Site) Lyase
Disease Progression
Drug Resistance, Neoplasm
Fibroblasts
Humans
Indoles
Male
Melanoma
Membrane Proteins
Mice
Microphthalmia-Associated Transcription Factor
Middle Aged
Molecular Targeted Therapy
Neoplasm Metastasis
Neovascularization, Pathologic
Oxidative Stress
Phenotype
Reactive Oxygen Species
Sulfonamides
Tumor Microenvironment
Vemurafenib
Wnt Signaling Pathway
Wnt1 Protein
beta Catenin
English 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.
Language
  • English
Open access status
green
Identifiers
Persistent URL
https://sonar.ch/global/documents/47814
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