Despite the onset of new treatment strategies, mortality rates for breast cancer are estimated at approximately 600,000 women per year, mostly due to acquired resistance to therapy. Chemotherapy, often combination therapy, includes DNA-damaging agents such as epirubicin, an epimer of doxorubicin. Although chemotherapy has been reported to reduce recurrence rates by 50% over two years, eight-year survival rates are approximately 30% and overall mortality is 20-25%. Studies aiming to overcome resistance to therapy have focused mainly on in vitro malignant cell assays. These have failed to deliver appropriate targets to overcome resistance because they have failed to account for the influence of the tumor microenvironment on chemoresistance. Published evidence indicates that resistance to therapy is not malignant cell-intrinsic, but instead depends on DNA-damaging chemotherapy-induced changes in paracrine signals from endothelial cells. Our current research has established that the doxorubicin treatment acutely affects endothelial cells with long-term effects on tumor cell resistance to therapy in vivo. Endothelial cells are heterogenous, and the effect of DNA damage on endothelial cell evolution and how this regulates malignant cell resistance to therapy is unknown. We have observed that orthotopic murine mammary tumors arising from the same source of primary mammary tumor cells show differential chemotherapy responses. RNA seq analysis of tumors after acute doxorubicin treatment reveal highest levels of differential transcript expression in endothelial cells compared with cancer-associated fibroblasts or malignant cells. In vitro assays show that conditioned media from tumor endothelial cells treated with chemotherapy can protect tumor cells from DNA damage and cell death. Current analysis now focuses on analyzing the complexity of endothelial cell regulation of tumor cell response to chemotherapy and how this could model clonal evolution of tumor cells. We aim to create a chemoresistance stromal evolution signature, to determine the individual components of this and commonalities between cancers and possible drug effects. Thus, our data could change the paradigm of drug resistance and define how stromal compartments regulate acquired resistance.

Citation Format: Jesus Gomez-Escudero, Eleni Maniati, Freddie Whiting, Jun Wang, Trevor Graham, Kairbaan Hodivala-Dilke. Tumor stroma in the development of acquired cancer therapy resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A31.