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

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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Figure 1: TNC expression in lung metastatic foci and association with lung relapse.
Figure 2: Cancer cell–derived TNC mediates resistance to apoptosis in micrometastasis.
Figure 3: Expression of TNC and stem cell markers in oncospheres.
Figure 4: Regulation of oncosphere growth, MSI1 and LGR5 by TNC.
Figure 5: TNC enhances WNT and NOTCH signaling in breast cancer cells.
Figure 6: TNC association with STAT5 and Musashi in breast cancer metastasis.

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Acknowledgements

We thank J. Kim and E. Montalvo for technical support. This work was funded by grant CA94060 from the US National Institutes of Health (J.M.), the Hearst Foundation and the Alan and Sandra Gerry Metastasis Research Initiative. S.A. is supported by a Department of Defense Era of Hope postdoctoral fellowship. E.B. is a recipient of the Exceptional Project Award from the Breast Cancer Alliance. J.M. is an investigator of the Howard Hughes Medical Institute.

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T.O. and J.M. designed experiments, analyzed data and wrote the manuscript. J.M. supervised research. T.O. carried out experiments. S.A. carried out immunostaining and helped with pathway analyses. X.H.-F.Z. carried out bioinformatics analyses. S.V. carried out intracardiac injections and assisted with bone and brain metastasis assays. S.F.T. helped with miRNA analysis. P.G.M. and R.J.D. oversaw collection of clinical samples. K.M.-T. supervised histological staining and analysis. E.B. obtained and evaluated human breast cancer tissue sections. All authors discussed the results and commented on the manuscript.

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Correspondence to Joan Massagué.

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The authors declare no competing financial interests.

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Oskarsson, T., Acharyya, S., Zhang, XF. et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 17, 867–874 (2011). https://doi.org/10.1038/nm.2379

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