Role of LRG1 in colorectal cancer tumorigenesis

Patients with metastatic colorectal cancer (mCRC) have substantially worse outcomes than those with primary and localized CRC. Over 80% of CRC metastases occur in the liver, which has a unique endothelial cell (EC)- rich microenvironment. Distinct from precedent EC studies focused on angiogenesis and vascular remodeling, we discovered that liver ECs secrete soluble factors to promote mCRC development in a paracrine fashion. Specifically, we found that human epidermal growth factor receptor 3 (HER3, also known as Erbb3) is a key mediator of EC-induced mCRC growth in the liver. However, we found that liver ECs activate HER3 independent of the only known HER3 ligand, neuregulins. Here, we made the paradigm-shifting discovery that leucine rich alpha-2-glycoprotein 1 (LRG1) secreted from liver ECs is a novel HER3 ligand that activates CRC-associated HER3 and promote CRC cell growth. Moreover, systemic inhibition of LRG1 attenuates the growth of CRC subcutaneous (subQ) xenografts and increases mouse survival in an orthotopic mCRC model. The GOAL of this proposal is to determine the role of LRG1 as a novel HER3 ligand in promoting mCRC development, and to elucidate the mechanisms by which LRG1 binds and activates HER3. We HYPOTHESIZE that LRG1 is a novel HER3 ligand and that the LRG1-HER3 signaling axis plays a critical role in CRC liver metastases development. We will test this hypothesis in two SPECIFIC AIMS: Aim 1 will determine roles of EC-secreted LRG1 in promoting mCRC initiation and outgrowth in clinically relevant mCRC models with EC-specific LRG1 knockout mice, a LRG1 neutralizing antibody, and patient-derived xenografts and organoids. Aim 2 will elucidate the mechanisms by which LRG1 binds and activate HER3, and determined the correlations between HER3 activation and mCRC patient outcomes. INNOVATIONS of this project include determination of a novel role of LRG1 in promoting mCRC development, identification of LRG1 as a novel HER3 ligand, and elucidation of the mechanisms of LRG1 activating HER3. Successful completion of the proposed studies will also identify HER3 activation as a potential prognostic biomarker for patients with mCRC, and lay a foundation for developing new therapeutic strategies for targeting LRG1 and other amenable component(s) in the LRG1-HER3 signaling cascade.