Abstract 1288: NRP1 exon 4-skipping variant promotes colorectal cancer metastasis by secreted exosomes and activated endosomal signals

Abstract

Abstract Neuropilin-1 (NRP1) is a transmembrane glycoprotein that acts as a critical co-receptor for tyrosine kinase receptors in growth factor signaling in both physiological and pathological context. The characterization of the NRP1 variants generated by alternative splicing mechanisms has provided profound insights into our understanding of the regulation of NRP1 function in cancer growth, angiogenesis, invasion and metastasis as well as for the modulation of therapeutic outcomes. Here, we identified a novel human NRP1 splice variant resulting from the skipping of exon 4 (NRP1-ΔE4) in colorectal cancer (CRC). We found that NRP1-ΔE4 was largely expressed in CRC and significantly correlated with CRC progression. Furthermore, NRP1-ΔE4 exhibited increased endocytosis/recycling activity via secreted exosomes and decreased levels of degradation, leading to accumulation on endosomes. In addition, NRP1-ΔE4 enhanced interactions with the Met and β1-integrin receptors, resulting in Met/β1-integrin co-internalization and co-accumulation on endosomes. This provided persistent endosomal signals to activate the FAK/p130Cas pathway, thereby promoting CRC cell migration, invasion and metastasis. Blocking exosome secretion, endocytosis or endosomal Met/β1-integrin/FAK signaling using genetic and pharmacological approaches profoundly inhibited the oncogenic effects of NRP1-ΔE4. Taken together, these findings reveal a unique function of NRP1-ΔE4 in the regulation of endocytic trafficking for CRC cell dissemination. Citation Format: Yiwei Gu, Xiuping Huang, Qing Ye, Qing-Bai She. NRP1 exon 4-skipping variant promotes colorectal cancer metastasis by secreted exosomes and activated endosomal signals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1288.