Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment.
The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here, we report that neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin that promote α5β1 integrin-dependent fibronectin fibril assembly, matrix stiffness, and tumor growth. Tumor growth and fibronectin fibril assembly were reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo. Mechanistically, the increase in fibronectin fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl that augmented α5β1 fibronectin fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of fibronectin fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment.
Gastroenterology Research Unit and Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Usman
U
Yaqoob
Sheng
S
Cao
Uday
U
Shergill
Kumaravelu
K
Jagavelu
Zhimin
Z
Geng
Meng
M
Yin
Thiago M
TM
de Assuncao
Ying
Y
Cao
Anna
A
Szabolcs
Snorri
S
Thorgeirsson
Martin
M
Schwartz
Ju Dong
JD
Yang
Richard
R
Ehman
Lewis
L
Roberts
Debabrata
D
Mukhopadhyay
Vijay H
VH
Shah
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes; D002460:Cell Line; D045744:Cell Line, Tumor; D005353:Fibronectins / Q000096:biosynthesis* / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059016:Tumor Microenvironment
D005353:Fibronectins; D039081:Integrin alpha5beta1; D039942:Neuropilin-1