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Biotechnol."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma and profound spatial heterogeneity, yet the multicellular organizational principles governing its tumor microenvironment remain poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq;\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20099) and spatial transcriptomics (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20094), integrating 61,234 single cells and 30,430 spots to identify an invasive-frontier myofibroblastic cancer-associated fibroblast (IF-myCAF), which is characterized by elevated expression of\n                    <jats:italic>ACTA2<\/jats:italic>\n                    ,\n                    <jats:italic>TAGLN<\/jats:italic>\n                    ,\n                    <jats:italic>COL11A1<\/jats:italic>\n                    ,\n                    <jats:italic>THBS2<\/jats:italic>\n                    ,\n                    <jats:italic>CTHRC1<\/jats:italic>\n                    , and\n                    <jats:italic>POSTN<\/jats:italic>\n                    . IF-myCAFs were validated in eight independent PDAC cohorts (159 samples with 67,959 CAFs), showing conserved transcriptional programs and representing a major CAF subpopulation across datasets. Spatial cellular community (CC) analysis identified five recurrent CCs that delineated the multicellular organization of PDAC. Notably, the invasive-desmoplastic CC (ID-CC), which localized to the tumor-stroma interface, was defined by a 5.8-fold enrichment of IF-myCAF; within this community, IF-myCAF colocalized with malignant ductal cells and macrophages. We also found that the ID-CC transcriptional signature was independently associated with worse outcome in TCGA-PAAD. Furthermore, ligand-receptor (LR) analysis of 4,009 IF-myCAF-associated LR pairs identified IF-myCAF as the predominant cell population mediating ECM-related intercellular signaling within ID-CC. Structure-based virtual screening against four IF-myCAF-derived ligand-receptor axes mediating intercellular communication within this community (THBS2-CD47, CTHRC1-FZD8, PPIA-BSG\/CD147, MIF-CD74) identified five multi-target drug-repurposing candidates, including conivaptan, lonafarnib, rucaparib, desloratadine, and ketotifen. Collectively, this study first identified a novel CAF subpopulation, IF-myCAF, and established a CC-based organizational scheme for PDAC spatial architecture. Our findings advance our understanding of spatial ecosystem-level stromal heterogeneity in PDAC and suggest targeting IF-myCAF-driven signaling within ID-CC.\n                  <\/jats:p>","DOI":"10.1007\/s44307-026-00141-8","type":"journal-article","created":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T21:34:39Z","timestamp":1791668079000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial multi-omics uncovers an invasive-desmoplastic cellular community with prognostic and therapeutic implications in pancreatic ductal adenocarcinoma"],"prefix":"10.1007","volume":"4","author":[{"given":"Chang-Hao","family":"Liang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Ping","family":"Lian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue-Qin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3913-4455","authenticated-orcid":false,"given":"Wen-Tao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,10]]},"reference":[{"key":"141_CR1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","volume":"630","author":"J Abramson","year":"2024","unstructured":"Abramson J, Adler J, Dunger J, Evans R, Green T, Pritzel A, et al. 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