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Studies in developmental models suggest that TNC may regulate the Wnt signaling pathway. Our laboratory has shown high levels of Wnt signaling and TNC expression in anaplastic thyroid cancer (ATC), a highly lethal cancer with an abysmal approximately 3- to 5-month median survival. Here, we investigated the role of TNC in facilitating ligand-dependent Wnt signaling in thyroid cancer. We used bulk RNA-sequencing from 3 independent multi-institutional thyroid cancer patient cohorts. TNC expression was spatially localized in patient tumors with RNA in situ hybridization. The role of TNC was investigated in vitro using Wnt reporter assays and in vivo with a NOD.PrkdcscidIl2rg\u2013\/\u2212 mouse ATC xenograft tumor model. TNC expression was associated with aggressive thyroid cancer behavior, including anaplastic histology, extrathyroidal extension, and metastasis. Spatial localization of TNC in patient tissue demonstrated a dramatic increase in expression within cancer cells along the invasive edge, adjacent to Wnt ligand\u2013producing fibroblasts. TNC expression was also increased in areas of intravascular invasion. In vitro, TNC bound Wnt ligands and potentiated Wnt signaling. Finally, in an ATC mouse model, TNC increased Wnt signaling, tumor burden, invasion, and metastasis. Altogether, TNC potentiated ligand-driven Wnt signaling and promotes cancer cell invasion and metastasis in a mouse model of thyroid cancer. Understanding the role of TNC and its interaction with Wnt ligands could lead to the development of novel biomarkers and targeted therapeutics for thyroid cancer.<\/jats:p>","DOI":"10.1210\/endocr\/bqaf030","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T13:44:51Z","timestamp":1739540691000},"source":"Crossref","is-referenced-by-count":10,"title":["Tenascin-C Potentiates Wnt Signaling in Thyroid Cancer"],"prefix":"10.1210","volume":"166","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6985-355X","authenticated-orcid":false,"given":"Heather A","family":"Hartmann","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A","family":"Loberg","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George J","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna C","family":"Schwarzkopf","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Vanderbilt University , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheau-Chiann","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney J","family":"Phifer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kailey","family":"Caroland","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua-Chang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Diaz","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan L","family":"Tigue","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda B","family":"Hesterberg","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Nicolas","family":"Gallant","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head & Neck Surgery, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia M","family":"Shaddy","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8951-9295","authenticated-orcid":false,"given":"Quanhu","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James L","family":"Netterville","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head & Neck Surgery, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L","family":"Rohde","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head & Neck Surgery, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen C","family":"Sol\u00f3rzano","sequence":"additional","affiliation":[{"name":"Department of Surgery, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay A","family":"Bischoff","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naira","family":"Baregamian","sequence":"additional","affiliation":[{"name":"Department of Surgery, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula J","family":"Hurley","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]},{"name":"Department of Urology, Vanderbilt University , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara A","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer H","family":"Choe","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Vanderbilt University , Nashville, TN 37232 ,","place":["USA"]},{"name":"Department of Pharmacology, Vanderbilt University , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0874-3207","authenticated-orcid":false,"given":"Vivian L","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]},{"name":"Department of Cell and Developmental Biology, Vanderbilt University , Nashville, TN 37232 ,","place":["USA"]},{"name":"Department of Otolaryngology\u2014Head & Neck Surgery, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["USA"]},{"name":"Department of 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