LRG1 is a novel ligand of HER3 and promotes metastatic colorectal cancer growth

Abstract

Therapy failure for patients with metastatic colorectal cancer (mCRC) remains an overarching challenge in the clinic. We find that liver endothelial cells secrete soluble factor(s) to promote mCRC growth in vitro and in vivo. We identify LRG1 in ECs secretome, which promotes growth in tumor cells through binding and activation of HER3. Pharmacological blocking of the LRG1/HER3 axis using LRG1 antibody 15C4 completely attenuated LRG1-induced HER3 activation and in vitro and in vivo growth of the tumor. Moreover, LRG1-/- mice with CRC allografts in the liver had 2 times longer overall survival than tumor-bearing LRG1+/+ mice. Lastly, unbiased -omics analysis and target-specific inhibitors identified eIF4-protein synthesis is significantly activated by the LRG1/HER3/RSK1/2 axis. This work reveals a paracrine mechanism of mCRC growth in liver microenvironment and highlighted the potential of blocking LRG1-HER3 and involved downstream pathways for treating patients with mCRC. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/529070v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1a84299org.highwire.dtl.DTLVardef@1ac6654org.highwire.dtl.DTLVardef@1723260org.highwire.dtl.DTLVardef@4970a8_HPS_FORMAT_FIGEXP M_FIG C_FIG