Authors and affiliations:
Sayan Chakraborty1, Manikandan Lakshmanan1, Hannah L. F. Swa1, Jianxiang Chen1,2, Xiaoqian Zhang1, Yan Shan Ong1, Li Shen Loo1, Semih Can Akıncılar1, Jayantha Gunaratne1, Vinay Tergaonkar1, Kam M. Hui1,2 and Wanjin Hong1
1 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61, Biopolis Drive, Proteos, Singapore, 138673.
2 Laboratory of Cancer Genomics, Cellular and Molecular Research Division, National Cancer Center Singapore, 11, Hospital Drive, Singapore 169610.
Published in Nature Communications on 29 January 2015
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths globally. The identity and role of cell surface molecules driving complex biological events leading to HCC progression are poorly understood, hence representing major lacunae in HCC therapies. Here, combining SILAC quantitative proteomics and biochemical approaches, we uncover a critical oncogenic role of Agrin, which is overexpressed and secreted in HCC. Agrin enhances cellular proliferation, migration and oncogenic signaling. Mechanistically, Agrin’s extracellular matrix sensor activity provides oncogenic cues to regulate Arp2/3 dependant ruffling, invadopodia formation and epithelial-mesenchymal transition through sustained focal adhesion integrity that drives liver tumorigenesis. Furthermore, Agrin signaling through Lrp4-Muscle specific tyrosine kinase (MuSK) forms a critical oncogenic axis. Importantly, antibodies targeting Agrin reduced oncogenic signaling and tumor growth in vivo. Together, we demonstrate that Agrin is frequently up-regulated and important for oncogenic property of HCC and is an attractive target for antibody therapy.
Figure Legend: A working model describing the role of Agrin in HCC. Overexpression of secreted and cell surface Agrin triggers elevated binding to its receptors Lrp4 and promotes the formation of the Agrin-Lrp4-MuSK signalling complex, which activates focal adhesions (FAK activation), Arp2/3 associated components and cortactin generating ruffling and invadopodia. This ECM sensor activity of Agrin is critical for sustaining FAK activity, cell motility, invasiveness, matrix degradation and subsequent mesenchymal marker recruitment to cell membrane. Internalized Agrin and its complex may also mediate signalling at the endosomal compartments. Cumulatively, these Agrin mediated events are essential for hepatic tumorigenesis.
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