Funding
Basic Research Laboratory (BRL)
Lustgarten Foundation (Lustgarten)
American Heart Association (AHA)
Air Force Surgeon General (Surgeon General of the Air Force)
ARTICLE ABSTRACT
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.
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.
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.
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.
