{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:55:09Z","timestamp":1790603709936,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","issue":"54","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82573113"],"award-info":[{"award-number":["82573113"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai Municipality","doi-asserted-by":"publisher","award":["23ZR1454800"],"award-info":[{"award-number":["23ZR1454800"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Tumor budding (TB), defined as single tumor cells or small clusters (\u22644 cells) at the invasive front, is a strong adverse prognostic feature in oral squamous cell carcinoma (OSCC). However, the stromal regulators and molecular mechanisms that drive TB remain unclear. Here, we developed a tumor\u2010budding organoid (TBO) model that faithfully recapitulates the OSCC tumor\u2010stroma interface and budding dynamics. By integrating this model with single\u2010cell RNA sequencing (scRNA\u2010seq), in situ RNA sequencing (isRNA\u2010seq), and functional perturbations, we identify platelet\u2010derived growth factor receptor alpha\n                    <jats:sup>+<\/jats:sup>\n                    \/integrin \u03b12\n                    <jats:sup>+<\/jats:sup>\n                    (PDGFR\u03b1\n                    <jats:sup>+<\/jats:sup>\n                    \/integrin \u03b12\n                    <jats:sup>+<\/jats:sup>\n                    ) cancer\u2010associated fibroblasts (CAFs) as the key stromal subset promoting OSCC budding. OSCC cells recruit PDGFR\u03b1\n                    <jats:sup>+<\/jats:sup>\n                    CAFs through PDGFA\/PDGFR\u03b1 signaling. These CAFs engage OSCC cells through two complementary crosstalk pathways: (1) heterotypic E\u2010cadherin\/integrin \u03b12\u03b21 adhesion that transmits biomechanical cues to activate YAP signaling and induce epithelial\u2010mesenchymal transition (EMT)\u2010like programs; and (2) tunneling nanotube (TNT)\u2010mediated mitochondrial transfer that enhances oxidative phosphorylation (OXPHOS) and bioenergetic supply in budding cells. Targeted inhibition of TNT\u2010mediated mitochondrial transfer markedly suppresses TB in TBO and xenograft models. Together, our results reveal a mechano\u2010metabolic symbiosis between PDGFR\u03b1\n                    <jats:sup>+<\/jats:sup>\n                    \/integrin \u03b12\n                    <jats:sup>+<\/jats:sup>\n                    CAFs and OSCC cells that drives TB and provides actionable targets to block this aggressive metastatic precursor.\n                  <\/jats:p>","DOI":"10.1002\/advs.76385","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T13:49:20Z","timestamp":1782827360000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PDGFR\u03b1\n                    <sup>+<\/sup>\n                    \/Integrin \u03b12\n                    <sup>+<\/sup>\n                    Fibroblasts Orchestrate Tumor Budding in Oral Squamous Cell Carcinoma via Mechano\u2010Metabolic Symbiosis: E\u2010Cadherin\/Integrin \u03b12\u03b21 Adhesion and Mitochondrial Transfer"],"prefix":"10.1002","volume":"13","author":[{"given":"Yufang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Oral Pathology Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Department of Orthodontics Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huibing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangning","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Department of Multidisciplinary Consultant Center Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Yang","sequence":"additional","affiliation":[{"name":"Intelligent Medicine Institute Shanghai Medical College Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5390-0382","authenticated-orcid":false,"given":"Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laiping","family":"Zhong","sequence":"additional","affiliation":[{"name":"Huashan Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Ji","sequence":"additional","affiliation":[{"name":"Zhongshan Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingjiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological Hospital &amp; School of Stomatology Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21293"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/JS9.0000000000001953"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010020\u20100422\u2010y"},{"key":"e_1_2_10_5_1","first-page":"6111","article-title":"Tumor Budding, EMT and Cancer Stem Cells in T1\u20102\/N0 Oral Squamous Cell Carcinomas","volume":"35","author":"Attramadal C. G.","year":"2015","journal-title":"Anticancer Research"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2017.01.015"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/hed.25872"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2017.46"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14153571"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/hed.25462"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.425"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2023.188940"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010022\u201000531\u20109"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010019\u20100238\u20101"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222111960"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010025\u201001688\u20100"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.09.015"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010021\u201000546\u20105"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.03.004"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.18063\/ijb.v7i4.444"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9LC00135B"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13040654"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.08.015"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31653"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21176225"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201020\u20100129"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.08.011"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420\u2010023\u201001428\u20108"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12143"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.31557\/APJCP.2024.25.5.1477"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4550"},{"key":"e_1_2_10_32_1","first-page":"3555","article-title":"Further Studies on the Histological Characteristics Linked to Local Tumour Invasion in Colorectal Carcinomas","volume":"23","author":"Rubio C. A.","year":"2003","journal-title":"Anticancer Research"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.12602"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3478"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107382"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.76385","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.76385","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.76385","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T12:57:44Z","timestamp":1790600264000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.76385"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":34,"journal-issue":{"issue":"54","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/advs.76385"],"URL":"https:\/\/doi.org\/10.1002\/advs.76385","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]},"assertion":[{"value":"2026-03-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e76385"}}