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Cellular and Molecular Biology

Periostin–TGF-β feedforward loop contributes to tumour-stroma crosstalk in liver metastatic outgrowth of colorectal cancer

British Journal of Cancer volume 130, pages 358–368 (2024)Cite this article

Subjects

Abstract

Background

This study aimed to investigate the underlying mechanisms of matricellular protein periostin (POSTN) on tumour-stroma crosstalk in the liver metastatic microenvironment of colorectal cancer (CRC).

Methods

Postn-knockout mice and hepatic Postn-overexpressing mice were used to investigate the functions of POSTN on the formation of fibrotic microenvironment and the tumour-stroma crosstalk in the liver metastatic microenvironment of CRC. Clinical samples and database were analyzed to show the correlation between POSTN expression and fibrotic features and TGF-β signalling in metastatic livers of CRC.

Results

POSTN deficiency reduced hepatic stellate cell (HSC) activation and liver metastasis, whereas POSTN overexpression in the liver significantly augmented the formation of a fibrotic microenvironment to support the liver metastatic growth of CRC cells in mice. Moreover, HSC-derived POSTN promoted TGF-β1 expression in CRC cells through the integrin/FAK/ERK/STAT3 pathway; conversely, tumour cell-derived TGF-β1 induced POSTN expression in HSCs via the Smad pathway. POSTN levels correlated with fibrotic features and TGF-β signalling in metastatic liver tissues of CRC patients.

Conclusions

POSTN and TGF-β1 cooperatively contribute to the tumour-stroma crosstalk by forming a supporting fibrotic microenvironment to promote liver metastasis of CRC cells via the POSTN/integrin/FAK/ERK/STAT3/TGF-β axis in tumour cells and TGF-β/Smad/POSTN signalling in activated HSCs.

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Fig. 1: POSTN is highly expressed in the fibrotic metastatic microenvironment.
Fig. 2: POSTN deficiency reduces the fibrotic metastatic microenvironment formation and metastatic colonization of CMT93 colorectal tumour cells in the livers of C57BL/6 mice.
Fig. 3: POSTN deficiency reduces the fibrotic metastatic microenvironment formation and metastatic colonization of CT26 colorectal tumour cells in the livers of BALB/C mice.
Fig. 4: Overexpression of POSTN in the livers promotes the fibrotic metastatic microenvironment formation and metastatic growth of colorectal tumour cells.
Fig. 5: POSTN promotes the expression of TGF-β1 in CRC cells by activating the integrin/FAK/ERK/STAT3 pathway.
Fig. 6: TGF-β promotes POSTN expression in HSCs via the Smad signalling pathway.
Fig. 7: POSTN level correlates with fibrotic features and TGF-β signalling in metastatic liver tissues of CRC patients.

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Data availability

All data are present in the manuscript and the Supplementary Materials. Additional data related to this paper may be requested from the corresponding author.

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Acknowledgements

We are deeply grateful to Prof. Xiaoying Li for providing recombinant adenoviruses and Dr. Fan Liu and Dr. Dan Cui for their valuable support.

Funding

This work was supported by grants from the National Natural Science Foundation of China (81772616, 81470793, 81972748, 82172932, and 82273416) and the Natural Science Foundation of Fujian Province of China (2019J02002).

Author information

Author notes

  1. These authors contributed equally: Bin Liu, Tiantian Wu, Biyu Lin.

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China

    Bin Liu, Tiantian Wu, Biyu Lin, Xingxing Liu, Chuannan Fan & Gaoliang Ouyang

  2. Department of Hematology, the First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China

    Bin Liu, Tiantian Wu, Xingxing Liu, Yingfu Liu & Gaoliang Ouyang

  3. Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen, China

    Yingfu Liu & Gang Song

  4. Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands

    Chuannan Fan

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Contributions

BL, TW, BLin, XL and CF acquired experimental data. BL, TW, BLin, GS, CF and GO were involved in manuscript writing. BL, TW, BLin, YL, GS, CF and GO analyzed the data. TW, GS and GO obtained funding. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Gang Song, Chuannan Fan or Gaoliang Ouyang.

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The authors declare no competing interests.

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Human clinical samples were collected with informed consent from the patients. The collection and study of human clinical samples were performed in accordance with the approved guidelines of the Ethics and Scientific Committees of Xiamen Hospital of Traditional Chinese Medicine.

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Liu, B., Wu, T., Lin, B. et al. Periostin–TGF-β feedforward loop contributes to tumour-stroma crosstalk in liver metastatic outgrowth of colorectal cancer. Br J Cancer 130, 358–368 (2024). https://doi.org/10.1038/s41416-023-02516-3

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