ZIP1-dependent lymphatic adaptations facilitate lymph node metastasis of pancreatic cancer

Tumor disseminates through lymphatic vessels to form lymph node (LN) metastasis, which requires lymphatic adaptations. However, it remains largely unknown how lymphatic vessels adapt to the stimuli causing LN metastasis of pancreatic cancer. Zinc dyshomeostasis has been observed in various tumors, including pancreatic cancer. We hypothesize that lymphatic vessels actively adapt to zinc imbalance, and examine lymphatic functions and LN metastasis of transplanted pancreatic cancer in zinc transporter ZIP1 deficient mice. The results show that ZIP1 is required for lymphatic glycolysis and junctional adaptations that facilitate LN metastasis of pancreatic cancer. In Zip1^-/- mice, the opening of lymphatic barrier and LN metastasis of pancreatic cancer are both mitigated. Inhibition of ZIP1 decreases Zn²⁺ influx and increases tight junction protein Claudin-5 in lymphatic endothelial cells, thereby suppressing tumor trans-endothelial migration. Mechanistically, ZIP1 promotes lymphatic glycolysis to produce lactic acids which impair Claudin-5 expression. Furthermore, in lymphatic-specific Zip1 knockout mice, lymphatic barrier is tightened and LN metastases are reduced. Importantly, ZIP1⁺ lymphatics are positively associated with LN metastasis of human pancreatic cancer. Taken together, these findings suggest that ZIP1-dependent metabolic and junctional adaptations in lymphatics accelerate LN metastasis of pancreatic cancer, providing potential therapeutic targets for pancreatic cancer metastasis.