This study reveals that endothelial cell-secreted LRG1 acts as a novel HER3 ligand, activating a non-canonical HER3 signaling pathway to promote liver metastatic colorectal cancer growth. Targeting LRG1 significantly suppresses tumor progression and extends survival, offering a new therapeutic strategy for mCRC.
Literature Overview
The article "LRG1 promotes metastatic colorectal cancer growth through HER3 signaling," published in the journal Gastroenterology, reviews and summarizes the molecular mechanisms by which liver microenvironmental endothelial cells in metastatic colorectal cancer (mCRC) secrete LRG1 to activate the HER3 signaling pathway in cancer cells, thereby promoting tumor growth. The study reveals a neuregulin-independent HER3 activation pathway and demonstrates that blocking LRG1 effectively inhibits the growth of liver metastases and extends survival in animal models. This finding provides a fresh perspective on overcoming the failure of current HER3-targeted therapies and identifies a potential therapeutic target. The article further elucidates the critical role of the downstream PI3K-PDK1-RSK-eIF4B signaling axis, expanding our understanding of the HER3 signaling network.Background Knowledge
Colorectal cancer is the second leading cause of cancer-related deaths worldwide, with approximately 80% of metastatic cases occurring in the liver. The 5-year survival rate for mCRC remains as low as 14%, and treatment options are limited, particularly in terms of effective targeted strategies. HER3 (ErbB3), a member of the EGFR family, has been widely reported to promote tumor cell survival and drug resistance in various cancers. Its classical activating ligand, neuregulin, activates the PI3K-AKT and MAPK pathways through heterodimerization. However, despite over 20 HER3-targeting antibodies entering clinical trials, none have achieved significant efficacy, leading to the temporary abandonment of this target. Recent studies have found that endothelial cells in the liver microenvironment can activate HER3 via paracrine mechanisms independent of neuregulin, suggesting the existence of unknown non-canonical activation pathways. LRG1 (leucine-rich alpha-2-glycoprotein 1) is a protein secreted by endothelial cells known to play roles in angiogenesis and inflammation, but its function in the tumor microenvironment remains unclear. This study focuses on the crosstalk between the liver metastatic microenvironment and cancer cells, aiming to uncover potential mechanisms underlying sustained HER3 activation in mCRC, thereby providing a theoretical basis for developing more effective therapeutic strategies.
Research Methods and Experiments
Researchers utilized a co-culture system of patient-derived liver endothelial cells (ECs) and colorectal cancer (CRC) cells to investigate EC-CRC paracrine interactions. Soluble factors secreted by ECs that activate HER3 were screened using conditioned medium (CM) treatment, fast protein liquid chromatography (FPLC) fractionation, and mass spectrometry analysis. HER3 extracellular domain (ECD) was used in pull-down assays to enrich binding proteins, and candidate molecules were validated using recombinant proteins. siRNA and antibody-mediated LRG1 knockdown or neutralization experiments were performed to evaluate their effects on HER3 phosphorylation and cell proliferation. In animal models, subcutaneous xenograft (subQ) and orthotopic liver injection metastasis models were established. LRG1 knockout mice and the neutralizing antibody 15C4 were used to assess tumor growth and mouse survival. Global phosphoproteomics combined with pathway analysis identified the downstream signaling pathway of LRG1-HER3, and the function of the PI3K-PDK1-RSK-eIF4B axis was validated using specific inhibitors and siRNA.Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to identify LRG1 as a novel functional ligand of HER3, defining a non-canonical HER3 signaling pathway that challenges the traditional paradigm of HER3 activation dependent on neuregulin. This finding explains why antibodies targeting the neuregulin-HER3 interaction have been ineffective in the clinic and suggests that future efforts should focus on developing inhibitors targeting LRG1 or the LRG1-HER3 interface. As a secreted protein, LRG1 is a highly attractive therapeutic target, and antibodies against it are already in early clinical development (e.g., Magacizumab), enabling rapid translational potential.
Additionally, the study highlights the critical role of the tumor microenvironment in driving therapy resistance, suggesting that targeting cancer cells alone may be insufficient to overcome paracrine survival signals. Combination therapies targeting both cancer cells and the microenvironment (e.g., LRG1 antibody + HER3 inhibitor) may offer greater efficacy. Future studies should further validate the universality of LRG1 in liver metastases of other cancers and explore its potential as a biomarker, such as whether p-HER3 Y1289 or serum LRG1 levels can predict treatment response.
Conclusion
This study systematically elucidates a novel mechanism by which liver microenvironmental endothelial cells promote metastatic colorectal cancer growth through LRG1-mediated activation of HER3 in cancer cells. As a high-affinity ligand of HER3, LRG1 triggers the PI3K-PDK1-RSK-eIF4B signaling axis to enhance protein synthesis and tumor progression. This pathway operates independently of the classical AKT/ERK routes and is not blocked by existing HER3 antibodies. Animal experiments confirm that targeting LRG1 significantly inhibits metastatic tumor growth and extends survival, underscoring its substantial potential as a therapeutic target. This work not only provides a new treatment strategy for mCRC but also reinvigorates the clinical relevance of HER3 as an anticancer target. Future efforts should advance anti-LRG1 therapies into clinical trials and explore their application in other cancers reliant on the liver microenvironment. Additionally, biomarkers based on LRG1 or p-HER3 should be developed to guide precision therapy. This discovery marks a significant shift from a "cancer cell-centric" to a "microenvironment-cooperative" treatment paradigm.
