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Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance

Author

Listed:
  • Fei Chen

    (Chinese Academy of Sciences)

  • Qilai Long

    (Fudan University)

  • Da Fu

    (Tongji University School of Medicine)

  • Dexiang Zhu

    (Fudan University)

  • Yan Ji

    (Chinese Academy of Sciences)

  • Liu Han

    (Chinese Academy of Sciences)

  • Boyi Zhang

    (Chinese Academy of Sciences)

  • Qixia Xu

    (Chinese Academy of Sciences)

  • Bingjie Liu

    (Fudan University)

  • Yan Li

    (Chinese Academy of Sciences)

  • Shanshan Wu

    (Chinese Academy of Sciences)

  • Chen Yang

    (Chinese Academy of Sciences)

  • Min Qian

    (Chinese Academy of Sciences)

  • Jianmin Xu

    (Fudan University)

  • Suling Liu

    (Fudan University)

  • Liu Cao

    (China Medical University)

  • Y. Eugene Chin

    (Soochow University Medical College)

  • Eric W.-F. Lam

    (Imperial College London)

  • Jean-Philippe Coppé

    (University of California)

  • Yu Sun

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Washington)

Abstract

Chemotherapy and radiation not only trigger cancer cell apoptosis but also damage stromal cells in the tumour microenvironment (TME), inducing a senescence-associated secretory phenotype (SASP) characterized by chronic secretion of diverse soluble factors. Here we report serine protease inhibitor Kazal type I (SPINK1), a SASP factor produced in human stromal cells after genotoxic treatment. DNA damage causes SPINK1 expression by engaging NF-κB and C/EBP, while paracrine SPINK1 promotes cancer cell aggressiveness particularly chemoresistance. Strikingly, SPINK1 reprograms the expression profile of cancer cells, causing prominent epithelial-endothelial transition (EET), a phenotypic switch mediated by EGFR signaling but hitherto rarely reported for a SASP factor. In vivo, SPINK1 is expressed in the stroma of solid tumours and is routinely detectable in peripheral blood of cancer patients after chemotherapy. Our study substantiates SPINK1 as both a targetable SASP factor and a novel noninvasive biomarker of therapeutically damaged TME for disease control and clinical surveillance.

Suggested Citation

  • Fei Chen & Qilai Long & Da Fu & Dexiang Zhu & Yan Ji & Liu Han & Boyi Zhang & Qixia Xu & Bingjie Liu & Yan Li & Shanshan Wu & Chen Yang & Min Qian & Jianmin Xu & Suling Liu & Liu Cao & Y. Eugene Chin , 2018. "Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance," Nature Communications, Nature, vol. 9(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06860-4
    DOI: 10.1038/s41467-018-06860-4
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    Cited by:

    1. Yuli Chen & Qiuhui Li & Xiang Yu & Lu Lu & Zihan Zhou & Mingjie Li & Rui Xia & Xiongkang Gan & Yanming Hu & Guoqing Guo & Jiahao Guo & Hanyang Li & Qiunuo Li & Yanwen Liu & Xianghua Liu & Ming Sun, 2024. "The microprotein HDSP promotes gastric cancer progression through activating the MECOM-SPINK1-EGFR signaling axis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Ki-Fong Man & Lei Zhou & Huajian Yu & Ka-Hei Lam & Wei Cheng & Jun Yu & Terence K. Lee & Jing-Ping Yun & Xin-Yuan Guan & Ming Liu & Stephanie Ma, 2023. "SPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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