A new study by University of Kentucky Markey Cancer Center researchers provides new insight on targeted therapy for colorectal cancer metastasis.
Published in Nature Communications, the study focused on Neuropilin-1 (NRP1), a transmembrane protein that has been connected to the progression of cancers, particularly metastasis. The researchers identified two novel human NRP1 splice variants in colorectal cancer, both defective in N-linked glycosylation modification.
This defect leads to a constant amount of the NRP1 variants shuttling between the cell surface and the inside of the cell upon stimulation of HGF growth factor; it also leads to a decrease in the levels of NRP1 variants’ degradation so as to their accumulation on endosomes, the membrane-bound compartments inside a cell.
These NRP1 variants form a complex with MET and β1-integrin receptors and transport together with these receptors into endosomes. This complex provides persistent endosomal signals to activate the FAK/p130Cas pathway, thereby promoting colorectal cancer cell migration, invasion and metastasis. Additionally, the colorectal cancer cells that have formed NRP1 variants/MET/ β1-integrin complexes are resistant to drugs that inhibit MET tyrosine kinase activity, suggesting that colorectal cancer patients with these variants are likely to not respond to MET-targeted therapy.
The study was led by the lab of Qing-Bai She, associate professor in the UK Department of Pharmacology and Nutritional Sciences.
“These variants may serve as a predictive marker for colorectal cancer metastasis,” said She. “Our findings provide a new avenue of exploration by blocking internalization or formation of the NRP1 variants/Met/β1-integrin complexes or alternatively by inhibiting their endosomal signals on activation of FAK/p130Cas pathway for targeted therapies of colorectal cancer metastasis.”
This work was partially funded by the National Cancer Institute, the UK Markey Cancer Center, and the University of Kentucky Center for Clinical and Translational Sciences. Researchers from the Southern Medical University collaborated with UK scientists in this study.