Abstract 184: DNA damage response in quiescent fibroblasts elicits a distinct secretory program and confers acquired resistance to cancer therapies
Authors: Sun Yu , Coleman Ilsa , Plymate Stephen , Nelson Peter 
Published: May 2015

Cancer treatments including chemotherapy and radiation not only target neoplastic cells thus providing a favorable therapeutic index in early clinical stages, but generate a profound impact on benign cells of the tumor microenvironment (TME). In contrast to cancer cells, the majority of human somatic populations exist in a quiescence stage, which is characterized by reversible exit from the G0/G1 phase of cell cycle, and they can reenter the cell division cycle and continue proliferation under favorable conditions. In this study we sought to determine how quiescent cells respond to DNA-targeting agents originally utilized to kill cancer cells, and to establish the consequence of such alterations to the TME. The results of this study would have broad implications for physiology, cancer biology and targeted therapies. Using genome-wide microarrays, we examined the response of primary human prostate fibroblasts made quiescent by contact inhibition to ionizing radiation, and evaluated the pathological influence through an in vitro system of epithelial-stromal interactions. We found quiescent cells maintained an intact DNA damage response including formation of chromatin foci and although they entered senescence, the proliferative potential was reserved as determined by cell replicative growth surveillance. A secretory expression program based on DNA damage was developed in quiescent cells, termed QASP; this stress-response program was different from that of proliferative cells (DDSP) and the spectrums only partially overlapped. In each case, an intracellular signal transduction network activated by DNA damage repair activities, including but not limited to the mTOR pathway and NF-ΚB complex, emerged and was implicated in mediating a cascade of reactions that culminated in robust secretion, after acute cellular responses. Our data indicate the influence of secreted factors from damaged quiescent fibroblasts on prostate cancer (PCa) cells was comprehensive and significant. In particular, paracrine factors of damaged quiescent fibroblasts supported PCa resistance to cytotoxic therapies. Intriguingly, small molecular inhibitors targeting the mTOR pathway or NF-ΚB complex were able to abrogate secretion of vast majority of quiescent cell-derived effectors thereby minimizing the pathological consequences. To date, a primary barrier to treatment of advanced cancers is the ability of neoplastic cells to acquire resistance to cytotoxicity that results in circumvention of effective targeting. Defining mechanisms underlying drug resistance is critical for designing new therapeutic strategies to selectively bypass or restrain resistance pathways. As such, targeting QASP effectors or more systematically, resistance mechanisms engaged by TME, in conjunction with conventional therapies may improve clinical response to anti-cancer treatments and prolong the patient lifespan.

Citation Format: Yu Sun, Ilsa Coleman, Stephen Plymate, Peter Nelson. DNA damage response in quiescent fibroblasts elicits a distinct secretory program and confers acquired resistance to cancer therapies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 184. doi:10.1158/1538-7445.AM2014-184