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Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance

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Title: Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance
Authors: Lam, EW
Item Type: Journal Article
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.
Issue Date: 17-Oct-2018
Date of Acceptance: 18-Sep-2018
URI: http://hdl.handle.net/10044/1/63443
DOI: https://dx.doi.org/10.1038/s41467-018-06860-4
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 9
Copyright Statement: © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Cancer Research UK
Breast Cancer Now
Breast Cancer Now
Medical Research Council (MRC)
Funder's Grant Number: C37/A12011
2012NovemberPhD016
2012MayPR070
MR/N012097/1
Keywords: MD Multidisciplinary
Publication Status: Published
Article Number: 4315
Online Publication Date: 2018-10-17
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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