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CTHRC1 promotes liver metastasis by reshaping infiltrated macrophages through physical interactions with TGF-β receptors in colorectal cancer

Oncogene volume 40, pages 3959–3973 (2021)Cite this article

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Abstract

Metastasis is a major cause of cancer-related deaths. Tumor-intrinsic properties can determine whether tumor metastasis occurs or not. Here, by comparing the gene expression patterns in primary colorectal cancer (CRC) patients with or without metastasis, we found that Collagen Triple Helix Repeat Containing 1 (CTHRC1) in primary CRC served as a metastasis-associated gene. Animal experiments verified that CTHRC1 secreted by CRC cells promoted hepatic metastasis, which was closely correlated with macrophage infiltration. Depletion of macrophages by liposomal clodronate largely abolished the promoting effect of CTHRC1 on CRC liver metastasis. Furthermore, we demonstrated that CTHRC1 modulated macrophage polarization to M2 phenotypes through TGF-β signaling. A mechanistic study revealed that CTHRC1 bound directly to TGF-β receptor II and TGF-β receptor III, stabilized the TGF-β receptor complex, and activated TGF-β signaling. The combination treatment of CTHRC1 monoclonal antibody and anti-PD-1 blocking antibody effectively suppressed CRC hepatic metastasis. Taken together, our data demonstrated that CTHRC1 is an intrinsic marker of CRC metastasis and further revealed that CTHRC1 promoted CRC liver metastasis by reshaping infiltrated macrophages through TGF-β signaling, suggesting that CTHRC1 could be a potential biomarker for the early prediction of and a therapeutic target of CRC hepatic metastasis.

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Fig. 1: The metastasis-associated gene CTHRC1 is highly expressed in both primary colorectal cancer (CRC) and hepatic metastasis of CRC and predicts a poor prognosis.
Fig. 2: CTHRC1 derived from CRC cells promotes hepatic metastasis in a mouse model of CRC liver metastasis.
Fig. 3: CTHRC1 expression is closely correlated with M2 macrophage infiltration in the hepatic metastasis of CRC.
Fig. 4: CTHRC1 promotes hepatic metastasis of CRC in a macrophage-dependent manner in the mouse hepatic metastasis model.
Fig. 5: CTHRC1 promotes macrophage polarization to the M2 phenotype through TGF-β signaling in BMDMs.
Fig. 6: CTHRC1 directly interacts with extracellular components of TGF-β signaling and the ligand-receptor interaction of TGF-β signaling is enhanced by CTHRC1.
Fig. 7: The combination of CTHRC1 monoclonal antibody and anti-PD-1 monoclonal antibody attenuates the liver metastasis of CRC.

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Data availability

The RNA-seq data generated in this study have been deposited in the Sequence Read Archive (SRA) repository under accession code PRJNA669490 (for mouse) PRJNA714296 (for human). The authors declare that all the remaining data supporting the findings of this study are available within the article and its Supplementary information files or from the corresponding authors on reasonable request.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81802890 to X-LZ; No. 81902370 to S-HJ; No. 81871923 to JL; No. 31801212 to L-LY, No. 81872242 to Y-LZ), the Natural Science Foundation of Shanghai (No. 18ZR1436900 to X-LZ), the Shanghai Municipal Health Commission (No. 202040092 to X-LZ; No. 202040104, to Y-LZ; No. 201740105 to H-ZN), Program of Shanghai Academic/Technology Research Leader (No. 19XD1403400, to Z-GZ), Shanghai International Science and Technology Cooperation Fund (No. 18410721000, to Z-GZ), Excellent Academic Leader of Shanghai Municipal Health Bureau (No. 2018BR32, to Z-GZ), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (No. 20191809, to JL). We thank Dr Dong-Xue Li, Dr Shan Huang, Dr Li-li Zhu, Dr Shan Zhang, Yue Sun, and Kai-Xia Zhou for assistance with our experiments.

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  1. These authors contributed equally: Xue-Li Zhang, Li-Peng Hu, Qin Yang, Wei-Ting Qin

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Xue-Li Zhang, Li-Peng Hu, Qin Yang, Xu Wang, Guang-Ang Tian, Xiao-Mei Yang, Lin-Li Yao, Lei Zhu, Hui-Zhen Nie, Qing Li, Zhi-Gang Zhang, Yan-Li Zhang, Jun Li, Ya-Hui Wang & Shu-Heng Jiang

  2. Department of Radiation Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Wei-Ting Qin

  3. Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Chun-Jie Xu & Qing Xu

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Contributions

S-HJ conceived the project. Y-HW, JL, and Z-GZ designed experiments, and interpreted data in the manuscript. X-LZ, L-PH, W-TQ, XW, C-JX, G-AT, X-MY, Y-LZ, L-LY, LZ, H-ZN, and QL performed the experiments. QY performed bioinformatics analyses. X-LZ wrote the manuscript. S-HJ, Y-HW, JL, and Z-GZ edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yan-Li Zhang, Jun Li, Ya-Hui Wang or Shu-Heng Jiang.

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Zhang, XL., Hu, LP., Yang, Q. et al. CTHRC1 promotes liver metastasis by reshaping infiltrated macrophages through physical interactions with TGF-β receptors in colorectal cancer. Oncogene 40, 3959–3973 (2021). https://doi.org/10.1038/s41388-021-01827-0

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