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Cited by 869Cancer Cells and MetastasisDevelopmental Biology and Gene RegulationMechanisms of cancer metastasis

Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs

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Oskarsson, Thordur, Acharyya, Swarnali, Zhang, Xiang H-F, Vanharanta, Sakari, Tavazoie, Sohail F, Morris, Patrick G, Downey, Robert J, Manova-Todorova, Katia +2 more·2011·Nature Medicine
DOI 10.1038/nm.2379PMC PMC4020577
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Abstract

We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell-derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 (MSI1) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). MSI1 is a positive regulator of NOTCH signaling, whereas LGR5 is a target gene of the WNT pathway. TNC modulation of stem cell signaling occurs without affecting the expression of transcriptional enforcers of the stem cell phenotype and pluripotency, namely nanog homeobox (NANOG), POU class 5 homeobox 1 (POU5F1), also known as OCT4, and SRY-box 2 (SOX2). TNC protects MSI1-dependent NOTCH signaling from inhibition by signal transducer and activator of transcription 5 (STAT5), and selectively enhances the expression of LGR5 as a WNT target gene. Cancer cell-derived TNC remains essential for metastasis outgrowth until the tumor stroma takes over as a source of TNC. These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche.

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  • De novo activation of fibroblasts at secondary sites favours establishment of macrometastases via multiple mechanisms including production of tenascin and periostin.

    “Once cancer cells have disseminated, the de novo activation of fibroblasts at secondary sites favours the establishment of macrometastases via multiple mechanisms, including the production of matrix components such as tenascin and periostin that provide supporting signals to the cancer cells94,95.”

    From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [95]

    The Results section reports activated fibroblasts in late metastatic foci and stromal tenascin C (TNC) in large lung nodules; the Discussion says TNC from infiltrating myofibroblasts accumulates as nodules expand (page numbers unavailable). This supports the tenascin component, but the paper does not show that de novo fibroblast activation causes macrometastases or that these fibroblasts produce periostin. (LLM, conf=0.85)

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Authors
Oskarsson, T., Acharyya, S., Zhang, X. H.-F., Vanharanta, S., Tavazoie, S. F., Morris, P. G., Downey, R. J., Manova-Todorova, K., Brogi, E., & Massagué, J.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Massagué, Joan
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2011-06-26
Volume
17
Issue
7
Pages
867-874
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.2379
PMC
PMC4020577
OpenAlex
W2106572080
Cited by
869
References
5
Citations by year
2026: 23 · 2025: 27 · 2024: 38 · 2023: 53 · 2022: 49 · 2021: 69 · 2020: 75 · 2019: 62 · 2018: 59 · 2017: 63 · 2016: 70 · 2015: 82 · 2014: 65 · 2013: 66 · 2012: 57
FWCI
31.06
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (P01CA129243, P01CA094060, CA94060, P30CA008748)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
tenascin-C, breast cancer metastasis, lung metastasis, metastatic niche, extracellular matrix, Notch signaling, Wnt signaling, MSI1, Lgr5, cancer stem cells, micrometastases, STAT5, Nanog, Oct4, SOX2, tumor stroma
MeSH terms
Animals, Breast Neoplasms, Female, Lung Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Apoptosis, Tenascin, Receptors, G-Protein-Coupled, STAT5 Transcription Factor, Wnt Proteins, Mice, Receptors, Notch

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