Core Viewpoint - The study reveals a critical mechanism in colorectal cancer metastasis, where tumor cells transition from relying on paracrine signals to establishing an autocrine feedback loop through GREM1 and ACVR1C, enabling them to gain signaling autonomy and drive metastasis [3][9][12]. Group 1: Mechanism of Metastasis - GREM1 from the stroma binds to the new receptor ACVR1C in tumor epithelial cells, activating the SMAD2/3 signaling axis, inducing epithelial-mesenchymal transition (EMT), and promoting endogenous GREM1 transcription, forming a self-sustaining feedback loop [3][6]. - The study identifies a significant spatiotemporal transition of GREM1 expression from stromal cells in early-stage colorectal cancer to high expression in tumor epithelial cells in late-stage metastasis, correlating with poor patient prognosis [6][9]. - GREM1's affinity for ACVR1C is 67.7 nM, over 12 times that of its classical ligand Activin B, establishing GREM1 as a dominant ligand for ACVR1C [6][7]. Group 2: Therapeutic Implications - The research suggests that GREM1 is a promising therapeutic target, but traditional monoclonal antibody strategies may pose systemic side effects due to GREM1's role in physiological processes [7][9]. - A designed peptide (ACVR1C peptide) competes with GREM1 for binding to ACVR1C, showing significant inhibition of colorectal cancer liver metastasis in vivo, indicating a clear direction for clinical translation [7][11]. - The findings provide a new perspective on targeting the self-reinforcing oncogenic signaling loop in metastatic colorectal cancer, offering a selective intervention strategy [9][12].