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Cited by 180Cancer Cells and MetastasisTGF-β signaling in diseasesPancreatic and Hepatic Oncology Research

Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness

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Avgustinova, Alexandra, Iravani, Marjan, Robertson, David, Fearns, Antony, Gao, Qiong, Klingbeil, Pamela, Hanby, Andrew M., Speirs, Valerie +3 more·2016·Nature Communications
DOI 10.1038/ncomms10305PMC PMC4735631
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Abstract

Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease. However, the mechanisms underlying the tumour:fibroblast crosstalk that drive the intertumoural stromal heterogeneity remain poorly understood. Using in vivo models we identify Wnt7a as a key factor secreted exclusively by aggressive breast tumour cells, which induces CAF conversion. Functionally, this results in extracellular matrix remodelling to create a permissive environment for tumour cell invasion and promotion of distant metastasis. Mechanistically, Wnt7a-mediated fibroblast activation is not dependent on classical Wnt signalling. Instead, we demonstrate that Wnt7a potentiates TGFβ receptor signalling both in 3D in vitro and in vivo models, thus highlighting the interaction between two of the key signalling pathways in development and disease. Importantly, in clinical breast cancer cohorts, tumour cell Wnt7a expression correlates with a desmoplastic, poor-prognosis stroma and poor patient outcome.

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  • The αSMA-high, matrix-producing-high state is reversible, supported by the responsiveness of matrix production and the αSMA promoter to extracellular cues including substrate stiffness.

    “the responsiveness of matrix production by fibroblasts and the αSMA promoter to a range of extracellular cues, including substrate stiffness, supports the idea that the αSMA-high, matrix producing-high state is reversible63,64,137–139.”

    From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [138]

    The Results section (‘Wnt7a-driven CAF conversion is TGFβ-signalling-dependent’; page not provided) reports that Wnt7a increased fibroblast αSMA on hydrogels but not on rigid culture plastic, supporting responsiveness to mechanical context. It also reports cue-dependent collagen-gel contraction and remodelling. The passages do not establish that the αSMA-high, matrix-producing-high state reverses, or directly measure αSMA promoter activity or matrix production in response to substrate stiffness. (LLM, conf=0.84)

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Authors
Avgustinova, A., Iravani, M., Robertson, D., Fearns, A., Gao, Q., Klingbeil, P., Hanby, A. M., Speirs, V., Sahai, E., Calvo, F., & Isacke, C. M.
Affiliations
  • Institute of Cancer Research (GB)
  • University of Leeds (GB)
  • The Francis Crick Institute (GB)
Corresponding author
Isacke, Clare M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-01-18
Volume
7
Issue
1
Pages
10305-10305
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms10305
PMC
PMC4735631
OpenAlex
W2299095671
Cited by
180
References
1
Citations by year
2026: 7 · 2025: 11 · 2024: 13 · 2023: 20 · 2022: 11 · 2021: 28 · 2020: 30 · 2019: 18 · 2018: 15 · 2017: 19 · 2016: 8
FWCI
10.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Francis Crick Institute (10144)
  • Cancer Research UK (15154)
  • National Institute for Health and Care Research
  • Breast Cancer Campaign
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Keywords
Wnt7a, cancer-associated fibroblasts, breast cancer, tumor stroma, extracellular matrix remodeling, tumor invasion, metastasis, TGF-beta signaling, desmoplasia, tumor aggressiveness, tumor microenvironment
MeSH terms
Animals, Breast Neoplasms, Female, Fibroblasts, Humans, Mice, Inbred BALB C, Gene Expression Regulation, Neoplastic, NIH 3T3 Cells, Wnt Proteins, Mice

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