Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance

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, Eric W.-F. Lam, Jean-Philippe Coppé and Yu Sun ()
Additional contact information
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

Nature Communications, 2018, vol. 9, issue 1, 1-19

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06860-4

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