title: 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.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Thordur
authors.initials: T
authors.lastname: Oskarsson
authors.forename: Swarnali
authors.initials: S
authors.lastname: Acharyya
authors.forename: Xiang H-F
authors.initials: XH
authors.lastname: Zhang
authors.forename: Sakari
authors.initials: S
authors.lastname: Vanharanta
authors.forename: Sohail F
authors.initials: SF
authors.lastname: Tavazoie
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Morris
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Downey
authors.forename: Katia
authors.initials: K
authors.lastname: Manova-Todorova
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D051880:Receptors, Notch / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D019063:Tenascin / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D051880:Receptors, Notch; D050799:STAT5 Transcription Factor; D019063:Tenascin; D051153:Wnt Proteins