Abstract B009: Invasion status parses composition of the human pancreatic cancer perineural niche

Abstract

The peripheral nervous system innervates the pancreatic ductal adenocarcinoma (PDAC) microenvironment, and perineural invasion (PNI) of cancer cells correlates with metastatic burden and poor outcomes. Though PDAC innervation is near-universal and the majority of PDAC patients harbor PNI, the cellular and molecular composition of the heterocellular perineural niche is largely unknown, obscuring functional significance. Here we provide a spatial and molecular map of the human PDAC perineural niche, and a comparison of invaded versus non-invaded nerve neighborhoods. This multimodal map leverages a novel vision-centric artificial intelligence model for imaging-based spatial transcriptomics, coupled with pathology-guided single-nucleus RNA-seq. These analyses revealed that invaded nerve neighborhoods harbor cancer cells of the classical subtype, together with myofibroblastic cancer-associated fibroblasts (CAFs) and lipid-associated macrophages. Non-invaded nerve neighborhoods, in contrast, harbor inflammatory CAFs and infiltration of B and T lymphocytes. These findings suggests that PNI and not innervation itself is immune-suppressive in this setting, motivating functional studies.