Agenda

Tumor innervation is increasingly recognized as a driver of cancer progression. Yet, the mechanisms that drive neural growth into tumors remain poorly understood. The aim of my PhD research was to investigate the role of stromal stiffness in regulating sensory innervation in pancreatic cancer. Using two transgenic mouse models, which recapitulate the development and progression of human pancreatic ductal adenocarcinoma (PDAC), I demonstrated that pro-tumorigenic peptidergic sensory axons undergo extensive sprouting within PDAC tumors. The majority of these axons localize to the tumor stroma—a region characterized by elevated stiffness due to dense networks of crosslinked collagen fibers. I showed that adult sensory neurons isolated from dorsal root ganglia extended longer neurites when cultured on polyacrylamide substrates mimicking PDAC stiffness, compared to those mimicking normal pancreatic tissue. Similarly, on ex vivo pancreatic cancer slices, neurites extended longer on tumor regions than on adjacent non-tumorous tissue. This preferential growth was mediated by the mechanosensitive ion channel Piezo2. Collectively, these findings uncover a previously unrecognized role of Piezo2 in sensory neuron plasticity and suggest that the mechanical properties of the tumor microenvironment are key regulators of PDAC innervation.