A paracrine-to-autocrine shunt of GREM1 fuels colorectal cancer metastasis via ACVR1C

BACKGROUND: Tumor cells typically rely on paracrine stromal signals to guide malignant behavior, yet whether they gain signaling autonomy and thereby reduce microenvironment dependency during metastasis remains unclear. METHODS: Gremlin 1 (GREM1) and activin A receptor type 1C (ACVR1C) expression levels and cellular distribution were analyzed by immunohistochemistry, immunofluorescence (IF) staining, and single-cell transcriptomics in colorectal cancer (CRC) specimens across stages I-IV. The GREM1-ACVR1C interaction was identified and validated by interaction proteomics, co-immunoprecipitation, IF, and microscale thermophoresis (MST). Functional roles of the GREM1-ACVR1C axis in epithelial-mesenchymal transition (EMT) and metastasis were examined by transcriptomic profiling, pathway analysis, immunoblotting, reverse transcription quantitative PCR (RT-qPCR), scratch and transwell assays, and genetically engineered and xenograft mouse models. An inhibitory peptide targeting the GREM1-ACVR1C interface was designed and evaluated. RESULTS: While GREM1 remains restricted to stromal cells in earlier-stage (I-III) CRC, its ectopic expression in tumor epithelium increases markedly in stage IV. Mechanistically, we identify ACVR1C as a direct, high-affinity epithelial receptor for GREM1. Their interaction, independent of canonical transforming growth factor β receptor (TGFβR) and bone morphogenetic protein (BMP) signaling, activates SMAD2/3, which in turn induces the transcription of SNAI1 and GREM1, thereby establishing a self-sustaining autocrine loop that amplifies EMT. Disrupting this loop via stromal GREM1 deletion, epithelial ACVR1C knockdown, kinase inhibition, or a novel GREM1-blocking peptide targeting the GREM1-ACVR1C binding interface significantly impairs CRC metastasis in vivo. Remarkably, while stromal GREM1 is required to initiate this loop, epithelial-derived GREM1 is sufficient to maintain metastatic progression. Clinically, epithelial GREM1 or ACVR1C expression predicts aggressive disease and poor survival. CONCLUSIONS: Our findings define a paradigm wherein CRC cells hijack the stromal factor GREM1 to establish a tumor-autonomous GREM1-ACVR1C autocrine loop. This loop licenses signaling independence, drives sustained EMT, and represents a novel, actionable vulnerability in advanced CRC.