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Collagen I-DDR1 signaling promotes hepatocellular carcinoma cell stemness via Hippo signaling repression

Cell Death & Differentiation volume 30, pages 1648–1665 (2023)Cite this article

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Abstract

Cancer stem cells (CSCs) are a minority population of cancer cells with stemness and multiple differentiation potentials, leading to cancer progression and therapeutic resistance. However, the concrete mechanism of CSCs in hepatocellular carcinoma (HCC) remains obscure. We found that in advanced HCC tissues, collagen I was upregulated, which is consistent with the expression of its receptor DDR1. Accordingly, high collagen I levels accompanied by high DDR1 expression are associated with poor prognoses in patients with HCC. Collagen I-induced DDR1 activation enhanced HCC cell stemness in vitro and in vivo. Mechanistically, DDR1 interacts with CD44, which acts as a co-receptor that amplifies collagen I-induced DDR1 signaling, and collagen I-DDR1 signaling antagonized Hippo signaling by facilitating the recruitment of PP2AA to MST1, leading to exaggerated YAP activation. The combined inhibition of DDR1 and YAP synergistically abrogated HCC cell stemness in vitro and tumorigenesis in vivo. A radiomic model based on T2 weighted images can noninvasively predict collagen I expression. These findings reveal the molecular basis of collagen I-DDR1 signaling inhibiting Hippo signaling and highlight the role of CD44/DDR1/YAP axis in promoting cancer cell stemness, suggesting that DDR1 and YAP may serve as novel prognostic biomarkers and therapeutic targets in HCC.

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Fig. 1: Clinical significance of Collagen I and DDR1 in clinical HCC patients.
Fig. 2: Collagen I-DDR1 enhances the stemness of HCC.
Fig. 3: Collagen I-DDR1 enhances the stemness of HCC.
Fig. 4: CD44 interacts with DDR1 and facilitates DDR1 phosphorylation.
Fig. 5: CD44 cross-talking with DDR1 enhances HCC stemness in vitro and vivo.
Fig. 6: DDR1 impedes Hippo signaling through inactivating YAP.
Fig. 7: YAP cross-talking with DDR1 enhances HCC stemness in vitro and vivo.
Fig. 8: Co-inhibition of DDR1 and Hippo/YAP signaling impedes tumor proliferation and radiomics model of prediction on Collagen I expression.

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Data availability

Research data supporting this publication are available from the StarBase website [83]. All relevant data in this research are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank all study subjects for their participation in this study. Thanks to the Hubei BIOSSCI Biotech Co., Ltd for the technical support in IHC.

Funding

This study was supported by the National Natural Science Foundation of China (No. 81874149 to Wanguang Zhang; No. 82103606 to Xiaochao Zhang).

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  1. These authors contributed equally: Yi-xiao Xiong, Xiao-chao Zhang, Jing-han Zhu.

Authors and Affiliations

  1. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Yi-xiao Xiong, Xiao-chao Zhang, Jing-han Zhu, Yu-xin Zhang, Yong-long Pan, Yu Wu, Jian-ping Zhao, Jun-jie Liu, Yuan-xiang Lu, Hui-fang Liang, Zhan-guo Zhang & Wan-guang Zhang

  2. Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, Hubei, China

    Yi-xiao Xiong, Xiao-chao Zhang, Jing-han Zhu, Yu-xin Zhang, Yong-long Pan, Yu Wu, Jian-ping Zhao, Jun-jie Liu, Yuan-xiang Lu, Hui-fang Liang, Zhan-guo Zhang & Wan-guang Zhang

  3. Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China

    Yi-xiao Xiong, Xiao-chao Zhang, Jing-han Zhu, Yu-xin Zhang, Yong-long Pan, Yu Wu, Jian-ping Zhao, Jun-jie Liu, Yuan-xiang Lu, Hui-fang Liang, Zhan-guo Zhang & Wan-guang Zhang

  4. Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Xiao-chao Zhang

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Contributions

WGZ contributed to the conception. XCZ and WGZ contributed to the study design. HFL and ZGZ form the overarching research goals and aims. YXX and XCZ wrote the main manuscript text. YXX, JHZ, YXZ and YLP contributed to the acquisition, analysis, and interpretation of the data. WGZ supervised the research activity planning. JJL and YXL verified the results/experiments and other research outputs. WGZ support the finance of the project. YW and JPZ critically revised the manuscript. All authors read and approve the final manuscript.

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Correspondence to Hui-fang Liang, Zhan-guo Zhang or Wan-guang Zhang.

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Xiong, Yx., Zhang, Xc., Zhu, Jh. et al. Collagen I-DDR1 signaling promotes hepatocellular carcinoma cell stemness via Hippo signaling repression. Cell Death Differ 30, 1648–1665 (2023). https://doi.org/10.1038/s41418-023-01166-5

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