Abstract IA009: Profiling and targeting pancreatic cancer innervating neurons

Abstract

The peripheral nervous system (PNS) orchestrates organ function in health and disease. Many cancers, including pancreatic ductal adenocarcinoma (PDAC), are infiltrated by PNS neurons that contribute to the complexity of the tumor microenvironment (TME). However, the cell bodies of these neurons reside in distant PNS ganglia, causing cancer- or organ-innervating neurons to be largely absent from current tumor sequencing datasets. To molecularly characterize PDAC-innervating neurons at single-cell resolution, we developed Trace-n-seq, a strategy combining Fast Blue–mediated retrograde axonal tracing from tumors or healthy pancreas to their respective ganglia. Individual FB+ neurons are isolated from the ganglia by FACS and their transcriptomes established by single-cell RNA sequencing. Using this approach, we established transcriptomic profiles of >5,000 sympathetic and sensory neurons and >4,000 neurons innervating PDAC or healthy pancreas. Our analyses reveal previously unrecognized neuronal cell types and molecular networks that distinguish PDAC-innervating neurons from those associated with healthy pancreas or pancreatitis. Integration of neuronal and TME single-cell datasets delineates cancer-induced reprogramming of neuronal states, identifies a pancreatic cancer–nerve signature, and defines a neuro–cancer–microenvironment interactome. Functionally, pharmacological denervation induces a pro-inflammatory TME and enhances immune-checkpoint inhibitor efficacy. In addition, nab-paclitaxel induces intratumoral neuropathy by blocking sensory neuron activity, attenuating PDAC growth; when combined with sympathetic denervation, this approach results in synergistic tumor regression (Thiel et al., Nature, 2025). Together, our multidimensional analyses provide new insights into the networks and functions of pancreas- and PDAC-innervating neurons with direct clinical implications. These findings are being translated into SYNERGY, a multicenter phase I/II clinical trial combining targeting of celiac ganglion–derived innervating nerves, checkpoint-inhibitors and nab-paclitaxel.