RETRACTED ARTICLE: sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance
Open accessAbstract
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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In normal development and physiology, fibroblasts are the major producers of connective tissue ECM, with emerging data indicating that this function is modified with age.
“In normal development and physiology, fibroblasts are the major producers of connective tissue ECM, with emerging data indicating that this function is modified with age9,10.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [10]
The Abstract (page unavailable) reports age-related changes in dermal fibroblasts, including increased secretion of sFRP2 by aged fibroblasts. It does not say that fibroblasts are the major producers of connective-tissue ECM or that their ECM-producing function changes with age. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAging is a common risk factor for developing AD and cancer.
“Aging is a common risk factor for developing AD and cancer (6,7).”
From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [7]
The paper states in its main text (section labeled “Abstract”; page unavailable) that “Cancer is a disease of aging” and discusses age-related changes in melanoma. It does not address AD, so it supports only the cancer portion of the cited sentence. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCulture in 3D conditions can return fibroblasts to their original phenotype within tissue.
“several studies showing how culture in 3D conditions can return fibroblasts to their original phenotype within tissue10,142.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [10]
The Organotypic 3D Skin Reconstructs section describes placing fibroblasts in 3D skin reconstructs, and the passage labeled Abstract reports that they persisted there. Neither passage says that 3D culture returned fibroblasts to their original tissue phenotype; searches for that outcome found no supporting passage in our copy. No page numbers were provided. (LLM, conf=0.72)
Experimental — accuracy not yet measuredIncreased age-related sFRP2 secreted by fibroblasts promotes angiogenesis and metastasis of melanoma cells.
“The increased age-related sFRP2 secreted by fibroblasts also promoted angiogenesis and metastasis of melanoma cells [70].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [70]
The loose arrangement of the ECM in the aging microenvironment may be one of the causes of metastasis in elderly patients with tumors.
“As shown in Fig. 5, the loose arrangement of the ECM in the aging microenvironment may be one of the causes of metastasis in elderly patients with tumors [69, 70].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [70]
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References 30 · Cited by 398
Research works printed but not linked: 1
- Li G, Satyamoorthy K, Herlyn M. Dynamics of cell interactions and communications during melanoma development. Crit Rev Oral Biol Med. 2002; 13:62-70. [PubMed: 12097238]
- Authors
- 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., Lehrmann, E., Becker, K. G., Flaherty, K. T., Frederick, D. T., Wargo, J. A., Cooper, Z. A., Tetzlaff, M. T., Hudgens, C., Aird, K. M., Zhang, R., Xu, X., Liu, Q., Bartlett, E., Karakousis, G., Eroglu, Z., Lo, R. S., Chan, M., Menzies, A. M., Long, G. V., Johnson, D. B., Sosman, J., Schilling, B., Schadendorf, D., Speicher, D. W., Bosenberg, M., Ribas, A., & Weeraratna, A. T.
- Affiliations
- The Wistar Institute (US)
- University of Zurich (CH)
- National Institutes of Health (US)
- Yale University (US)
- Massachusetts General Hospital (US)
- The University of Texas MD Anderson Cancer Center (US)
- Abramson Cancer Center (US)
- City Of Hope National Medical Center (US)
- University of California, Los Angeles (US)
- Westmead Hospital (AU)
- The University of Sydney (AU)
- Vanderbilt University Medical Center (US)
- Essen University Hospital (DE)
- Corresponding author
- Weeraratna, Ashani T.
- ORCID
- Kaur, Amanpreet
- Webster, Marie R.
- Behera, Reeti
- Ndoye, Abibatou
- Dang, Vanessa M.
- O’Connell, Michael P.
- Cheng, Phil
- Morissette, Rachel
- Ferrucci, Luigi
- Kossenkov, Andrew V.
- Tang, Hsin-Yao
- Wood, William H.
- Lehrmann, Elin
- Becker, Kevin G.
- Flaherty, Keith T.
- Frederick, Dennie T.
- Wargo, Jennifer A.
- Cooper, Zachary A.
- Tetzlaff, Michael T.
- Hudgens, Courtney
- Aird, Katherine M.
- Zhang, Rugang
- Xu, Xiaowei
- Liu, Qin
- Bartlett, Edmund
- Karakousis, Giorgos
- Eroglu, Zeynep
- Lo, Roger S.
- Chan, Matthew
- Menzies, Alexander M.
- Long, Georgina V.
- Johnson, Douglas B.
- Sosman, Jeffrey
- Schilling, Bastian
- Schadendorf, Dirk
- Speicher, David W.
- Bosenberg, Marcus
- Ribas, Antoni
- Weeraratna, Ashani T.
- Venue
- Nature
- Published
- 2016-04-04
- Volume
- 532
- Issue
- 7598
- Pages
- 250-254
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4833579
- OpenAlex
- W2314266733
- Cited by
- 398
- References
- 30
- Citations by year
- 2026: 7 · 2025: 42 · 2024: 40 · 2023: 57 · 2022: 36 · 2021: 39 · 2020: 39 · 2019: 42 · 2018: 33 · 2017: 43 · 2016: 20
- FWCI
- 23.90
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- GlaxoSmithKline
- Johns Hopkins University
- Cancer Research UK
- National Institutes of Health
- University of California, San Francisco
- National Institute on Aging
- National Cancer Institute (T32 CA9171-36, P01CA114046, K99CA208012, R01CA174746, R01CA160331, P50CA093372, R01CA196660, P50CA174523, K12CA090625, R50CA211199, T32CA009171, P30CA010815)
- National Institute of General Medical Sciences (T32GM007324)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- SFRP2, melanoma metastasis, Wnt signaling, treatment resistance, vemurafenib, APE1, MITF, β-catenin, reactive oxygen species, angiogenesis, age-related cancer, retracted article
- MeSH terms
- Vemurafenib, Secreted Frizzled-Related Proteins, Adult, Aging, Animals, DNA Damage, Fibroblasts, Humans, Indoles, Male, Melanoma, Membrane Proteins, Middle Aged, Neoplasm Metastasis, Neovascularization, Pathologic, Phenotype, Sulfonamides, Culture Media, Conditioned, Reactive Oxygen Species, Oxidative Stress, Disease Progression, Drug Resistance, Neoplasm, DNA-(Apurinic or Apyrimidinic Site) Lyase, Cell Line, Tumor, Wnt1 Protein, beta Catenin, Mice, Microphthalmia-Associated Transcription Factor, Molecular Targeted Therapy, Tumor Microenvironment, Wnt Signaling Pathway
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