A paracrine-to-autocrine shunt of GREM1 fuels colorectal cancer metastasis via ACVR1C
Authors list
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 Junjing Zhang Xuetong Shen Tao Wang Youheng Jiang Ningning LiThis article is a preprint. Preprints have not been peer-reviewed.
You can read more about preprints.
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:
Colorectal cancer (CRC) specimens from stages I–IV were analyzed by immunohistochemistry and single-cell transcriptomics to assess GREM1 and ACVR1C expression and localization. The GREM1–ACVR1C interaction was validated by interaction proteomics, co-immunoprecipitation, immunofluorescence, and microscale thermophoresis (MST). Functional roles of the axis in metastasis were examined by transcriptomic profiling, pathway analysis, immunoblotting, 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 activin A receptor type 1C (ACVR1C) as a direct, high-affinity epithelial receptor for GREM1. Their interaction, independent of canonical TGFβR and BMP signaling, activates SMAD2/3, which in turn induces the transcription of SNAI1 and GREM1, thereby establishing a self-sustaining feedback loop that amplifies epithelial-mesenchymal transition (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. Clinically, epithelial GREM1 or ACVR1C expression predicts aggressive disease and poor survival.
Conclusions:
Our findings define a paradigm in which tumor cells hijack stromal GREM1 to establish a GREM1–ACVR1C autocrine loop that sustains EMT and metastasis, marking a shift toward signaling autonomy and revealing a targetable vulnerability in advanced CRC.
Details
Archive
Research Square
Available online
Publication date
Keywords
Type of publication
