{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:24:19Z","timestamp":1787217859871,"version":"build-2736575974"},"reference-count":37,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K08956"],"award-info":[{"award-number":["23K08956"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K02785"],"award-info":[{"award-number":["25K02785"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K12735"],"award-info":[{"award-number":["25K12735"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K20160"],"award-info":[{"award-number":["25K20160"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Lymph node (LN) metastasis is one of the major prognostic factors in head and neck squamous cell carcinoma (HNSCC), and treatment sensitivity often differs between primary tumors and metastatic LNs. Beyond tumor cell\u2013intrinsic differences, heterogeneity of the tumor microenvironment may contribute to these discrepancies. We focused on cancer\u2010associated fibroblasts (CAFs) and compared CAFs derived from primary tumors and corresponding LN metastases. Bulk tissue analysis showed higher expression of myofibroblast\u2010related genes (\n                    <jats:italic>ACTA2<\/jats:italic>\n                    ,\n                    <jats:italic>MYL9<\/jats:italic>\n                    ,\n                    <jats:italic>MYLK<\/jats:italic>\n                    ) and increased\n                    <jats:italic>COMP<\/jats:italic>\n                    expression in metastatic LNs. Thirteen paired CAFs were established and serially passaged. Compared with primary tumor\u2010derived CAFs (PT\u2010CAFs), metastatic LN\u2010derived CAFs (LN\u2010CAFs) exhibited reduced proliferative and migratory capacities, but enhanced collagen gel contraction, while promoting tumor cell\u2010sphere formation and cancer stem cell marker expression. These findings support a myofibroblast\u2010like phenotype in LN\u2010CAFs. In line with this, PT\u2010CAFs showed greater induction of myofibroblast\u2010related genes in response to TGF\u2010\u03b2, but not IL\u20106 stimulation, suggesting that LN\u2010CAFs had already differentiated toward a myofibroblast\u2010like phenotype. RNA sequencing of five paired CAFs confirmed a myofibroblastic transcriptional profile, with enrichment of fibrosis\u2010related and malignant trait\u2013associated pathways, including epithelial\u2013mesenchymal transition (EMT), hypoxia, and p53 signaling. Finally, least absolute shrinkage and selection operator\u2010based prognostic models validated in The Cancer Genome Atlas (TCGA) cohort using genes upregulated in LN\u2010CAFs were significantly associated with worse progression\u2010free survival and overall survival. These results demonstrate that CAF heterogeneity depends on tumor localization and is linked to therapeutic resistance and poor clinical outcomes in HNSCC.\n                  <\/jats:p>","DOI":"10.1111\/cas.70511","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T08:33:20Z","timestamp":1787214800000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Myofibroblast\u2010Like\n                    <scp>CAFs<\/scp>\n                    in Metastatic Lymph Nodes Drive Tumor Stemness and Poor Prognosis in Head and Neck Cancer"],"prefix":"10.1111","author":[{"given":"Hiroyuki","family":"Hagiwara","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Gunma University Graduate School of Medicine  Maebashi 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Graduate School of Medicine  Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7739-0102","authenticated-orcid":false,"given":"Kazuaki","family":"Chikamatsu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Gunma University Graduate School of Medicine  Maebashi 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