LRG1 is a novel HER3 ligand and promotes growth in colorectal cancer

Abstract

Abstract HER3 signaling pathway plays a major role in promoting the development of metastatic colorectal cancer (mCRC). Here, we demonstrated that endothelial cells, a key component of the liver microenvironment, secrete leucine-rich alpha-2-glycoprotein 1 (LRG1) that activates HER3 as a ligand, distinct from the canonical HER3 ligand neuregulins. Blocking LRG1 in host animals either by gene knockout or a neutralizing antibody significantly blocked outgrowth of CRC liver metastases and prolonged mouse survival. We also identified eIF4B-mediated protein synthesis as a downstream target of LRG1-HER3 interactions, and determined PI3K-PDK1-RSK as the mediating signaling axis. Our findings identify LRG1 as a key mediator of liver-mCRC crosstalk, and suggest inhibition of the LRG1-HER3 signaling axis as potential therapeutic strategy for treating patients with mCRC.