title: Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B.
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.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
authors.forename: Celestia
authors.initials: C
authors.lastname: Higano
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.forename: Peggy
authors.initials: P
authors.lastname: Porter
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.forename: Lawrence
authors.initials: L
authors.lastname: True
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D059016:Tumor Microenvironment / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D016328:NF-kappa B; C417262:WNT16 protein, human; D051153:Wnt Proteins