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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate below 10%. Cancer-associated fibroblasts (CAFs) promote epithelial\u2013mesenchymal transition (EMT) and metastasis, yet the specific CAF subtypes and molecular axes driving PDAC progression remain incompletely understood. Here, using multi-omics data from PDAC samples, we identified a malignant ductal subpopulation, termed Ductal-T0, characterized by the highest EMT activity and prominent acquisition of myofibroblastic CAF (myCAF)-like transcriptional programs. Computationally, we predicted that myCAF-secreted THBS2 and FN1 engage the ITGA3\/ITGB1\/SDC1\/SDC4 receptor axes in Ductal-T0 cells, which could activate TNF, NF-\u03baB, TGF-\u03b2, and PI3K-AKT-signaling pathways to promote EMT. Pseudotime trajectory and velocity analyses suggested that Ductal-T0 cells exhibited the highest propensity to acquire myCAF-like features among all ductal subpopulations. Survival analysis revealed that an increased proportion of Ductal-T0 cells and elevated abundance of THBS2-ITGA3\/ITGB1 and THBS2-SDC1 ligand\u2013receptor pairs were significantly associated with poor prognosis. Spatial transcriptomics further revealed that myCAFs and Ductal-T0 cells co-localized at the tumor margin, which may contribute to reduced immune cell presence via dense extracellular matrix (ECM) barrier formation\u2014a computationally inferred model of EMT-associated immune exclusion and metastatic progression\u2014and identify THBS2 as a promising candidate for future therapeutic investigation to disrupt CAF\u2013tumor crosstalk in PDAC.<\/jats:p>","DOI":"10.3390\/ijms27156951","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6951","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Myofibroblastic CAF and Malignant Ductal Cell Crosstalk Drives Epithelial\u2013Mesenchymal Transition and Progression in Pancreatic Ductal Adenocarcinoma via THBS2-SDC\/Integrin Axes"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8834-0779","authenticated-orcid":false,"given":"Zhonglu","family":"Ren","sequence":"first","affiliation":[{"name":"School of Medical Information and Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, China"},{"name":"Guangdong Province Precise Medicine Big Data of Traditional Chinese Medicine Engineering Technology Research Center, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuangchang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medical Information and Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, China"},{"name":"School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medical Information and Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medical Information and Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medical Information and Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Su","sequence":"additional","affiliation":[{"name":"School of Medical Information and Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medical Information and Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, China"},{"name":"Guangdong Province Precise Medicine Big Data of Traditional Chinese Medicine Engineering Technology Research Center, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,2]]},"reference":[{"key":"ref_1","first-page":"7","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. 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