LRP1 regulates GDNF secretion and perineural invasion in pancreatic cancer via PI3K/AKT signaling

Pancreatic cancer induces intense abdominal pain through the infiltration of cancer cells into surrounding nerve tissues, leading to sensory neuron damage. The research aims to identify pivotal molecules involved in PNI, contributing to clinical strategies that alleviate pain and enhance the quality of life for patients. This study used shRNA interference lentivirus to downregulate LRP1 expression in pancreatic cancer and neural cells, comparing perineural invasion (PNI) and neurotrophic factor level changes. An in vitro co-culture model of pancreatic cancer cells with dorsal root ganglia (DRG) assessed the impact of reduced LRP1 on DRG synaptic growth. Additionally, an animal model of neural invasion studied the effects of LRP1 downregulation on neural function. The mutual attraction between Panc-1 and SK-N-SH cells was suppressed upon the downregulation of LRP1 levels in both cell lines. Subsequent investigations revealed a reduction in the autocrine and paracrine secretion of neurotrophic factors and their receptors between Panc-1 and SK-N-SH with the decrease in LRP1 levels. At the tissue level, a significant inhibition of DRG growth was observed. The reduction of LRP1 expression effectively inhibits pancreatic cancer PNI. Concurrently, levels of neurotrophic factors and their receptors in the tumor-neural microenvironment decrease. Mechanistically, LRP1 knockdown suppressed PI3K/AKT and ERK signaling pathways, leading to reduced GDNF secretion and impaired perineural invasion. LRP1 may act as an important molecule in modulating communication between pancreatic cancer cells and neural tissues. Our study offers new potential targets for the treatment of pancreatic cancer neural invasion.