Epithelial–Mesenchymal Transition Is Associated With Perineural Invasion in Pancreatic Ductal Adenocarcinoma

Abstract

Introduction

Perineural invasion (PNI) is a high-risk feature of pancreatic ductal adenocarcinoma (PDAC) and is associated with aggressive behavior and poor outcomes. The biological programs associated with PNI in PDAC remain incompletely characterized.

Methods

PDAC patients in The Cancer Genome Atlas were stratified by PNI status. Gene set enrichment analysis using Hallmark gene sets was performed to characterize transcriptomic differences between PNI-positive and PNI-negative tumors. Established immune, proliferative, and genomic annotations curated from prior The Cancer Genome Atlas analyses were used for downstream comparisons.

Results

A total of 101 PNI-positive and 26 PNI-negative tumors were identified. PNI was associated with higher grade (P < 0.05). Gene set enrichment analysis demonstrated enrichment of multiple gene sets in PNI-positive tumors, including pathways related to cell proliferation (G2M checkpoint, mTORC1 signaling, E2F targets, MYC targets, and mitotic spindle), immune signaling (tumor necrosis factor-α signaling via NF-κB, interferon-α, and γ responses), and epithelial–mesenchymal transition (EMT). Yet, no differences were observed in measures of tumor proliferation, aggressiveness, mutational burden, immune response, or immune cell infiltration within the tumor microenvironment. In contrast, EMT enrichment was supported by concordant biological features, including increased infiltration of mesenchymal cells and elevated expression of EMT-associated genes in PNI-positive tumors.

Conclusions

PNI-positive PDAC demonstrate enrichment of EMT-related transcriptional programs with concordant microenvironmental and gene-level support.