Zhou, Huaixiang;
Jin, Qunlong;
Fu, Zhang;
Yang, Yanming;
Gao, Yunfei;
Wang, Niu;
Zhao, Bo;
... Li, Ningning; + view all
(2026)
A paracrine-to-autocrine shunt of GREM1 fuels colorectal cancer metastasis via ACVR1C.
Molecular Cancer
10.1186/s12943-025-02554-w.
(In press).
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | A paracrine-to-autocrine shunt of GREM1 fuels colorectal cancer metastasis via ACVR1C |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s12943-025-02554-w |
| Publisher version: | https://doi.org/10.1186/s12943-025-02554-w |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Colorectal cancer, EMT, GREM1–ACVR1C axis, Paracrine-to-autocrine shift, Signaling autonomy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10220904 |
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