Pancreatic cancer stromal heterogeneity characterized by multiplex immunohistochemistry-based image analyses

Abstract

Pancreatic cancer is characterized by an abundant desmoplastic stroma. Emerging evidence based on current technology, including single-cell transcriptomics, indicates that cancer-associated fibroblasts (CAFs) in human pancreatic cancer are phenotypically and functionally more heterogeneous than previously thought. Utilizing multiplex immunohistochemistry, we recently identified two mutually exclusive fibroblast subtypes defined by expression levels of α smooth muscle actin (αSMA) and fibroblast activation protein α (FAP) within pancreatic cancer tissues. In situ quantitative analyses of these fibroblast subtypes and collagen using formalin-fixed paraffin-embedded slides from 215 patients with treatment naïve pancreatic cancers manifested three distinct stroma types associated with differing prognoses and molecular pathological features. We introduce a multiplex image analysis-based quantitative system and discuss ①transcriptomic differences between the three pancreatic cancer stroma types and ②differences between non-tumor fibrosis and tumor-associated desmoplasia from the viewpoint of stromal composition of fibroblast subtypes and collagen.