TBC1D23 drives lymphatic metastasis in pancreatic ductal adenocarcinoma by altering EGFR cell surface dynamics and signaling

Abstract Rich in protein and adjacent to pancreatic cancer cells, pancreatic juice has been considered an attractive source to discover biomarkers for pancreatic ductal adenocarcinoma (PDAC). Here, we identified a novel biomarker, TBC1D23 in pancreatic juice of PDAC patients. High TBC1D23 expression was also observed in tumor tissues and sera, associated with lymphatic metastasis and shorter survival. TBC1D23 was strongly expressed in PDAC cell lines, and knocking down TBC1D23 reduced cell proliferation and migration in vitro and suppressed xenograft tumor growth and peritoneal metastasis in vivo. DNA microarray analysis identified the down-regulation of VEGF-C in TBC1D23 knockdown cells compared to control. Indeed, depletion of TBC1D23 decreased VEGF-C expression and secretion. Treatment with conditioned medium from PANC-1 cells promoted lymphangiogenesis in lymphatic endothelial cells, while this effect was counteracted by the VEGFR3 inhibitor MAZ51 or knockdown of TBC1D23, indicating that VEGF-C is a target gene of TBC1D23. Mechanistically, TBC1D23 could increase EGFR membrane distribution, enhance EGFR recycling, but inhibit EGFR endocytic degradation, suggesting that TBC1D23 up-regulates VEGF-C by maintaining EGFR capacity to transduce signals. This study clearly demonstrates the oncogenic role of TBC1D23 and EGFR/VEGF-C as its downstream signaling pathway for lymphatic metastasis.