Agenda

Advances in cancer neuroscience have demonstrated that the peripheral nervous system actively contributes to cancer progression rather than passively responding to it. Tumors reshape surrounding neuronal circuits, while neurons promote tumor growth through direct interactions and bioactive signals. This bidirectional crosstalk is particularly evident in pancreatic ductal adenocarcinoma (PDAC), where pro-tumorigenic sensory neurons undergo extensive remodeling within tumor lesions. Although targeting this neuronal plasticity shows therapeutic promise, the molecular cues driving PDAC innervation remain largely unknown. The aim of my PhD research was to identify secreted factors from PDAC cancer cells involved in the sensory innervation of pancreatic tumors. Using rodent dorsal root ganglia (DRG) nociceptor- and mechanoreceptor-like neurons cultured in organ-on-chip microfluidic devices and exposed to conditioned media (CM) from the human PDAC cell lines Panc1 and MiaPaCa2, I found that CM from Panc1 cells, but not MiaPaCa2 cells, promoted sensory axon outgrowth specifically in nociceptor-like neurons. A multi-omics analysis of publicly available datasets identified two secreted factors as candidate mediators of this effect: GDF15 (growth differentiation factor 15) and DKK1 (Dickkopf-1). Functional assays revealed that recombinant GDF15 and DKK1 increased axon length in rodent nociceptor-like neurons, whereas blocking these factors with the humanized neutralizing antibodies visugromab and sirexatamab reduced axon length in both rodent and human iPSC-derived sensory nociceptors. To evaluate whether this system could capture differential sensory neuron responses to clinically relevant tumor variants, I screened patient-derived PDAC cell lines and confirmed that GDF15 and DKK1 are clinically relevant candidates. GDF15 is broadly overexpressed and strongly associated with aggressive tumor subtypes and DKK1 correlates with gemcitabine resistance. Together, these findings demonstrate that PDAC cells stimulate pro-tumorigenic sensory axon remodeling through the release of GDF15 and DKK, two novel therapeutic targets that have the potential to both slow tumor progression and limit pathological innervation.