Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B

Yu Sun, Judith Campisi, Celestia Higano, Tomasz M. Beer, Peggy Porter, Ilsa Coleman, Lawrence True, Peter S. Nelson

    Research output: Contribution to journalArticle

    419 Scopus citations

    Abstract

    Acquired resistance to anticancer treatments is a substantial barrier to reducing the morbidity and mortality that is attributable to malignant tumors. Components of tissue microenvironments are recognized to profoundly influence cellular phenotypes, including susceptibilities to toxic insults. Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, we identified a spectrum of secreted proteins derived from the tumor microenvironment that includes the Wnt family member wingless-type MMTV integration site family member 16B (WNT16B). We determined that WNT16B expression is regulated by nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB) after DNA damage and subsequently signals in a paracrine manner to activate the canonical Wnt program in tumor cells. The expression of WNT16B in the prostate tumor microenvironment attenuated the effects of cytotoxic chemotherapy in vivo, promoting tumor cell survival and disease progression. These results delineate a mechanism by which genotoxic therapies given in a cyclical manner can enhance subsequent treatment resistance through cell nonautonomous effects that are contributed by the tumor microenvironment.

    Original languageEnglish (US)
    Pages (from-to)1359-1368
    Number of pages10
    JournalNature medicine
    Volume18
    Issue number9
    DOIs
    StatePublished - Sep 2012

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

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    Sun, Y., Campisi, J., Higano, C., Beer, T. M., Porter, P., Coleman, I., True, L., & Nelson, P. S. (2012). Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nature medicine, 18(9), 1359-1368. https://doi.org/10.1038/nm.2890