Deciphering transcriptional plasticity in pancreatic ductal adenocarcinoma reveals alterations in sensory neuron innervation.

Abstract

Neuronal innervation of the pancreas has historically been characterized using marker-based classification and physiological studies, but its transcriptomic landscape remains only partially explored. A detailed molecular profile of pancreatic sensory neurons could provide insights into their role in health and disease, particularly in pancreatic ductal adenocarcinoma (PDAC), where neural remodeling influences tumor progression and pain signaling. Wild-type and PDAC mice were injected with the retrotracer Fast Blue into pancreatic or cancerous tissue. Dorsal root ganglia were dissociated, and Fast Blue-positive sensory neurons were isolated, lysed, and analyzed using single-cell RNA sequencing. Data were validated using immunofluorescence, organoid cultures and qPCR. We performed transcriptomic profiling of sensory neurons innervating the pancreatic head and tail under normal and cancer conditions. Our analysis identified neurofilament-containing neurons as the predominant sensory subtype in both contexts, while non-peptidergic neurons were underrepresented in tumor-associated innervation. Differential gene expression analysis revealed a unique subset of genes upregulated in sensory neurons innervating pancreatic tumors, many linked to mitochondrial activity. Further validation also revealed the presence of transcripts transferred via extracellular vesicles (including the Pdx1-CreERT2 transgene from the KPC mouse model), suggesting a novel mechanism of tumor-neuron interaction. Our findings provide a detailed characterization of pancreatic and pancreatic ductal adenocarcinoma sensory innervation. We identified tumor-derived RNA within sensory neurons in the PDAC mouse model, suggesting an extracellular vesicle-mediated RNA transfer mechanism that may remodel sensory signaling and open new prospects for diagnostic and therapeutic innovation in PDAC. Impact statement Transcriptomic profiling of pancreatic sensory neurons reveals shifts in neuronal populations, tumor-specific mitochondrial gene upregulation, and potential extracellular vesicle-mediated transcript transfer. Circulating tumor transcripts in KPC mice provide a reference for pancreatic innervation, tumor-nerve interactions, and therapeutic targets.