Abstract P6-03-04: Microenvironment-induced epigenetic reprogramming imposes drug-tolerant states in breast cancer cells

Abstract

Abstract Development of resistance to breast cancer (BC) therapy is frustratingly common. Multiple mechanisms of resistance have been identified including selection of genetic resistance, redundant signaling, and others. More recently, rare cancer cells were shown to be sporadically reprogrammed by the presence of anti-cancer drugs into transiently resistant states, then to expand later after cessation of therapy. We have demonstrated that the physical character and composition of tumor microenvironment (ME) components are determinants of BC cell drug resistance, however, the mechanism by which this phenomenon occurs is unclear. We hypothesize that epigenetic reprogramming is not rare or sporadic, indeed, that specific tumor ME components impose epigenetic states that beget the expression of gene clusters that put cancer cells into drug-tolerant states. Our current pharmacopeia targets cancer cells, not their ME. Some tumor ME components, e.g. extracellular matrices (ECM), have half-lives that span years, and growth factors with typically short half-lives can be stabilized by direct association with ECM. Thus, a ME-imposed drug tolerance mechanism would explain how resistance can arise rapidly, in multiple locations, without the need for genetic selection. Because ME-cell interactions lead to activation of specific pathways, based on canonical receptor-ligand models, we should be able to circumvent ME-imposed drug tolerance by addition of molecules that alter ME-induced signaling. Clusters of genes that are activated in multidrug resistant breast cancer cells identified potential markers of drug tolerance. ME-drivers of the drug tolerance markers were identified in high-throughput cell-based screens with the MicroEnvironment MicroArray (MEMA) platform. BC cells were exposed in parallel to over 1000 unique combinatorial MEs, which were chosen to mimic normal mammary gland, and luminal or basal BC tumor MEs. Single-cell resolution analysis revealed MEs that induce and maintain drug-tolerance markers. Longer-term functional experiments validated that the identified MEs also increased BC cells drug tolerance. Chromatin accessibility profiling with ATAC-sequencing demonstrated that BC cells cultured in those drug-tolerance inducing MEs exhibit chromatin opening in promoter regions of genes linked to epithelial plasticity (e.g. Axl, SNAI2, Vimentin, TWIST1) within 24h of exposure. These results support the concept that specific MEs drive drug-tolerant cellular phenotypes and suggest a novel interventional avenue for preventing acquired therapy resistance. Citation Format: Tiina A Jokela, Dustin Schones, Mark A LaBarge. Microenvironment-induced epigenetic reprogramming imposes drug-tolerant states in breast cancer cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-04.