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.