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While most PTMCs exhibit indolent growth and a favorable prognosis, some undergo clinical progression with poor outcomes. Thus, identifying biomarkers associated with PTC, particularly those related to PTMC progression, is crucial for precise risk stratification and treatment planning. This study utilized single\u2010cell RNA sequencing on 19 surgical tissue specimens from 15 patients, including four para\u2010tumor tissues, four non\u2010progressive PTMCs, five progressive PTMCs, and six progressive PTCs. Key findings are corroborated through in vivo and in vitro experiments. Single\u2010cell RNA sequencing and spatial transcriptomics characterized the cellular ecosystem within PTC, revealing multi\u2010directional evolutionary patterns as PTMC progresses. Analysis of progression\u2010specific alterations in intercellular communication networks highlighted the PROS1\u2010MERTK signaling interaction as pivotal in PTMC progression. In vitro and in vivo models confirm that the PROS1\u2010MERTK axis accelerates PTMC progression via paracrine and autocrine signaling. Furthermore, NFYB and FOXP2 are identified as activators of PROS1 transcription in fibroblasts, promoting PTMC progression through the MERTK\/WNT\/TGF\u2010\u03b2 signaling. These findings underscore the PROS1\/MERTK axis as a critical component of the cellular microenvironment and a key regulatory mechanism in PTMC progression.<\/jats:p>","DOI":"10.1002\/advs.202413474","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T07:24:35Z","timestamp":1748417075000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["PROS1\u2010MERTK Axis Drives Tumor Microenvironment Crosstalk and Progression in Papillary Thyroid Microcarcinoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Wenqian","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Head and Neck Surgery Cancer Hospital of China Medical University Liaoning Cancer Hospital  Shenyang 110042 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Laboratory of Cancer Institute The First Hospital of China Medical University  Shenyang 110001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgery Cancer Hospital of China Medical University Liaoning Cancer Hospital  Shenyang 110042 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery The First Hospital of China Medical University  Shenyang 110001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaqin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Molecular Biology China Medical University  Shenyang 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery The First Hospital of China Medical University  Shenyang 110001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyue","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery The First Hospital of China Medical University  Shenyang 110001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery The First Hospital of China Medical University  Shenyang 110001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lirong","family":"Yan","sequence":"additional","affiliation":[{"name":"The First Laboratory of Cancer Institute The First Hospital of China Medical University  Shenyang 110001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Medicine Southern University of Science and Technology  Shenzhen 518055 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery The First Hospital of China Medical University  Shenyang 110001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1952-128X","authenticated-orcid":false,"given":"Wei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery The First Hospital of China Medical University  Shenyang 110001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,28]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-018-0068-3"},{"key":"e_1_2_9_2_1","first-page":"264","volume":"10","author":"Pizzato M.","year":"2022","journal-title":"Diabetes Endocrinol."},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/RLU.0b013e318279bc65"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.4158\/EP.13.5.498"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.f4706"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/JS9.0000000000001117"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.07.025"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.08.012"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-020-00727-5"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2018.00018"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbac234"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.21037\/gs-20-666"},{"key":"e_1_2_9_13_1","first-page":"2157","volume":"26","author":"Kucuk S.","year":"2021","journal-title":"J. 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