Human Pancreatic Cancer Single-Cell Atlas Reveals Association of CXCL10+ Fibroblasts and Basal Subtype Tumor Cells

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) patients basal subtype, correlating with worse overall survival in bulk RNA-with tumors enriched for the basal-like molecular subtype exhibit seq. Deconvolution identified one of the basal populations to be the enhanced resistance to standard-of-care treatments and have predominant tumor subtype in nondissociated ST tissues and significantly worse overall survival compared with patients with in vitro tumor cell and patient-derived organoid lines. We dis-classic subtype–enriched tumors. It is important to develop ge- covered a novel enrichment and spatial association of CXCL10+ nomic resources, enabling identification of novel putative targets cancer-associated fibroblasts with basal tumor cells. We identified in a statistically rigorous manner. that besides immune cells, ductal cells also express CXCR3, the Experimental Design: We compiled a single-cell RNA se- receptor for CXCL10, suggesting a relationship between these cell quencing (scRNA-seq) atlas of the human pancreas with 229 pa- types in the PDAC tumor microenvironment. tient samples aggregated from publicly available raw data. We Conclusions: We show that our scRNA-seq atlas (700,000 cells), mapped cell type–specific scRNA-seq gene signatures in bulk integrated with ST data, has increased statistical power and is a RNA-seq (n ¼ 744) and spatial transcriptomics (ST; n ¼ 22) and powerful resource, allowing for expansion of current subtyping performed validation using multiplex immunostaining. paradigms in PDAC. We uncovered a novel signaling niche Results: Analysis of tumor cells from our scRNA-seq atlas marked by CXCL10+ cancer-associated fibroblasts and basal tumor revealed nine distinct populations, two of which aligned with the cells that could be explored for future targeted therapies.