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

By Thordur Oskarsson, Swarnali Acharyya, X. Zhang, S. Vanharanta, S. Tavazoie, P. Morris, R. Downey, K. Manova-Todorova, E. Brogi, J. Massagué. Nature Medicine, 2011

824 citations recorded by the source corpus.

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.

Subfields: Immunology and Allergy, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/a09249b06aa143206c7d4ff57eae44576da0b22d

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Citations in the corpus

EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, neutral): “This idea is bolstered by the identification of specific ECM components, such as tenascin C (TNC) (Oskarsson et al., 2011) and POSTN (Malanchi et al., 2012) that drive colonization of the lung by breast carcinoma cells.”
Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 (2013, background): “In preclinical models, tenascin C promotes the aggressiveness of metastasis [41] and autocrine tenascin”
Tumor Metastasis: Molecular Insights and Evolving Paradigms (2011, neutral): “Finally, the ECM protein tenascin C is capable of stimulating metastatic colonization of the lung by breast cancer cells via perturbation of the Notch and Wnt signal transduction cascades, two circuitries that have previously been linked to the TIC phenotype (Oskarsson et al., 2011).”
Spherical Cancer Models in Tumor Biology (2015, methodology): “Although tumorospheres are characterized by the absence of stromal cells and the lack of exogenous ECM, it has been reported that cancer cells themselves within tumorospheres are able to produce ECM components like tenascin C to partially create their CSC niche [34].”
Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy (2015, neutral): “Tenascin C is a stromal marker previously reported to be induced in pancreatic cancer and has been implicated in metastasis in other cancer models (Juuti et al , 2004; Oskarsson et al , 2011).”
Dependency of colorectal cancer on a TGF-beta-driven programme in stromal cells for metastasis initiation (2012, background): “…prometastatic genes, such as ANGPTL4 (Padua et al., 2008), PTHLH (Yin et al., 1999), HBEGF (Bos et al., 2009), CTGF (Kang et al., 2003), TNC (Oskarsson et al., 2011), or JAG1 (Sethi et al., 2011; Sonoshita et al., 2011), all of which encode for secreted or membranebound factors (Table S4).”
CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma (2016, neutral): “…T cells (Feig et al., 2013) (Figure S2F), numerous activated a-smooth muscle actin (a-SMA)-positive stellate cells (Figure S2G), abundant levels of the pro-invasive protein tenascin C (Oskarsson et al., 2011) (Figure S2H), and high levels of tumor cell proliferation (marked by Ki67, Figure S2I).”
The Cancer Stem Cell Niche: How Essential is the Niche in Regulating Stemness of Tumor Cells? (2015, neutral): “The ECM component tenascin C (TNC) is found in stem cell niches, frequently supplied by CAFs and associated with increased risk of metastasis (Oskarsson et al., 2011).”
Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance (2019, background): “In particular, tenascin-C (TNC) was shown to be an integral component of the metastatic niche molded by breast cancer cells during lung colonization (Oskarsson et al., 2011), and later studies using a proteomic approach expanded the role of this matrix protein to lung cancer metastasis (Gocheva et a”