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PMID: 21706029 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

Nature medicine ·Vol. 17 ·No. 7 ·2011-06-26 ·Pages 867-74

Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Morris PG, Downey RJ, Manova-Todorova K, Brogi E, Massagué J

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.

MeSH Terms
Animals Apoptosis/physiology Breast Neoplasms/metabolism,pathology,physiopathology Female Gene Expression Regulation, Neoplastic/physiology Lung Neoplasms/secondary Mice Receptors, G-Protein-Coupled/metabolism Receptors, Notch/physiology STAT5 Transcription Factor/physiology Signal Transduction/physiology Tenascin/physiology Wnt Proteins/metabolism
Chemicals
Lgr5 protein, mouse Receptors, G-Protein-Coupled Receptors, Notch STAT5 Transcription Factor Tenascin Wnt Proteins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Oskarsson Thordur
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Acharyya Swarnali
Zhang Xiang H-F
Vanharanta Sakari
Tavazoie Sohail F
Morris Patrick G
Downey Robert J
Manova-Todorova Katia
Brogi Edi
Massagué Joan
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.2379
Published
2011-06-26
Epub
2011-00-26
Pages
867-74
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC4020577
Subset
IM
Grants
NCI NIH HHS · P01 CA094060 · United States
NCI NIH HHS · P01 CA129243 · United States
NCI NIH HHS · P30 CA008748 · United States
NCI NIH HHS · CA94060 · United States
External Links
PubMed source DOI: 10.1038/nm.2379 PMC Full Text View journal details
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