Human Pancreatic Cancer Single-Cell Atlas Reveals Association of CXCL10+ Fibroblasts and Basal Subtype Tumor Cells
Recommended Citation
Loveless IM, Kemp SB, Hartway KM, Mitchell JT, Wu Y, Zwernik SD, Salas-Escabillas DJ, Brender S, George M, Makinwa Y, Stockdale T, Gartrelle K, Reddy RG, Long DW, Wombwell A, Clark JM, Levin AM, Kwon D, Huang L, Francescone R, Vendramini-Costa DB, Stanger BZ, Alessio A, Waters AM, Cui Y, Fertig EJ, Kagohara LT, Theisen B, Crawford HC, and Steele NG. Human Pancreatic Cancer Single-Cell Atlas Reveals Association of CXCL10+ Fibroblasts and Basal Subtype Tumor Cells. Clin Cancer Res 2025; 31(4):756-772.
Document Type
Article
Publication Date
2-17-2025
Publication Title
Clinical cancer research
Abstract
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) patients with tumors enriched for the basal-like molecular subtype exhibit enhanced resistance to standard-of-care treatments and have significantly worse overall survival compared with patients with classic subtype-enriched tumors. It is important to develop genomic resources, enabling identification of novel putative targets in a statistically rigorous manner.
EXPERIMENTAL DESIGN: We compiled a single-cell RNA sequencing (scRNA-seq) atlas of the human pancreas with 229 patient samples aggregated from publicly available raw data. We mapped cell type-specific scRNA-seq gene signatures in bulk RNA-seq (n = 744) and spatial transcriptomics (ST; n = 22) and performed validation using multiplex immunostaining.
RESULTS: Analysis of tumor cells from our scRNA-seq atlas revealed nine distinct populations, two of which aligned with the basal subtype, correlating with worse overall survival in bulk RNA-seq. Deconvolution identified one of the basal populations to be the predominant tumor subtype in nondissociated ST tissues and in vitro tumor cell and patient-derived organoid lines. We discovered a novel enrichment and spatial association of CXCL10+ cancer-associated fibroblasts with basal tumor cells. We identified that besides immune cells, ductal cells also express CXCR3, the receptor for CXCL10, suggesting a relationship between these cell types in the PDAC tumor microenvironment.
CONCLUSIONS: We show that our scRNA-seq atlas (700,000 cells), integrated with ST data, has increased statistical power and is a powerful resource, allowing for expansion of current subtyping paradigms in PDAC. We uncovered a novel signaling niche marked by CXCL10+ cancer-associated fibroblasts and basal tumor cells that could be explored for future targeted therapies.
Medical Subject Headings
Humans; Chemokine CXCL10; Single-Cell Analysis; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Cancer-Associated Fibroblasts; Tumor Microenvironment; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Fibroblasts; Gene Expression Profiling; RNA-Seq; Transcriptome; Prognosis
PubMed ID
39636224
Volume
31
Issue
4
First Page
756
Last Page
772
