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Background <p> 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.</p> Methods <p>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.</p> Results <p>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 <i>SNAI1</i> and <i>GREM1</i>, thereby establishing a self-sustaining autocrine loop that amplifies EMT. Disrupting this loop via stromal GREM1 deletion, epithelial <i>ACVR1C</i> 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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月24日

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  • Huaixiang Zhou,
  • Qunlong Jin,
  • Zhang Fu,
  • Yanming Yang,
  • Yunfei Gao,
  • Niu Wang,
  • Bo Zhao,
  • Long Gui,
  • Jiang Li,
  • Zijing Zhu,
  • Ying Zhang,
  • Yulong He,
  • Ying Zhang,
  • Shouqing Luo,
  • Li Fu,
  • Xudong Wu,
  • Guihua Wang,
  • Zhiming Xu,
  • Huiliang Li,
  • Junjing Zhang,
  • Xuetong Shen,
  • Tao Wang,
  • Youheng Jiang,
  • Ningning Li

摘要

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.