Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment

Usman Yaqoob, Sheng Cao, Uday Shergill, Kumaravelu Jagavelu, Zhimin Geng, Meng Yin, Thiago M. De Assuncao, Ying Cao, Anna Szabolcs, Snorri Thorgeirsson, Martin Schwartz, Ju Dong Yang, Richard Ehman, Lewis Roberts, Debabrata Mukhopadhyay, Vijay H. Shah

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4047-4059
Number of pages13
JournalCancer research
Volume72
Issue number16
DOIs
StatePublished - Aug 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Yaqoob, U., Cao, S., Shergill, U., Jagavelu, K., Geng, Z., Yin, M., De Assuncao, T. M., Cao, Y., Szabolcs, A., Thorgeirsson, S., Schwartz, M., Yang, J. D., Ehman, R., Roberts, L., Mukhopadhyay, D., & Shah, V. H. (2012). Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment. Cancer research, 72(16), 4047-4059. https://doi.org/10.1158/0008-5472.CAN-11-3907