Human pancreatic cancer single cell atlas reveals association of CXCL10+ fibroblasts and basal subtype tumor cells.

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 (OS) compared to patients with classical 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 (scRNAseq) atlas of the human pancreas with 229 patient samples, aggregated from publicly available raw data. We mapped cell-type specific scRNAseq gene signatures in bulk RNAseq (n=744) and spatial transcriptomics (ST) (n=22) and performed validation using multiplex immunostaining.

Results: Analysis of tumor cells from our scRNAseq atlas revealed nine distinct populations, two of which aligned with the basal subtype, correlating with worse OS in bulk RNAseq. Deconvolution identified one of the basal populations to be the predominant tumor subtype in non-dissociated 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 (CAFs) 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 PDAC tumor microenvironment.

Conclusions: We show that our scRNAseq 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+ CAFs and basal tumor cells that could be explored for future targeted therapies.