Spatial multi-omics uncovers an invasive-desmoplastic cellular community with prognostic and therapeutic implications in pancreatic ductal adenocarcinoma
Open accessAbstract
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 = 9) and spatial transcriptomics ( n = 4), 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 ACTA2 , TAGLN , COL11A1 , THBS2 , CTHRC1 , and POSTN . 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.
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Flagged first, then by citations
- Authors
- Liang, C.-H., Ye, H., Xu, H., Fang, C., Lian, J.-P., Chen, Y.-Q., Wang, W.-T., & He, B.
- Affiliations
- Sun Yat-sen University (CN)
- Corresponding author
- He, Bo
- Venue
- Advanced Biotechnology
- Published
- 2026-10-10
- Volume
- 4
- Issue
- 4
- ISSN
- 2948-2801 (ISSN-L)
- PMC
- PMC13653914
- OpenAlex
- W7221328071
- Cited by
- 0
- References
- 42
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Advanced Biotechnology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (32370594, 81772621)
- National Key R&D Program of China (2022YFA1303302)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- pancreatic ductal adenocarcinoma, cancer-associated fibroblasts, tumor microenvironment, desmoplastic stroma, tumor-stroma interface, intercellular communication, ligand-receptor interactions, extracellular matrix, drug repurposing, prognostic signature, macrophages
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