Abstract 3133: Clonal facilitation drives estrogen receptor positive (ER+) breast cancer growth and survival

Competition between different lineages of cells within a tumor has been included in thinking about cancer evolution and progression, but positive interactions like cooperation have received far less study. We have developed isogenic estrogen positive breast cancer cell lineages sensitive and resistant to CDK4/6 inhibition in order to investigate the mechanisms cell interactions under selective pressure. When these sensitive and resistant lineages are grown in co-culture under ribociclib treatment, sensitive survive and proliferate better than in mono-culture despite the effects of competition. Conditioned media taken from resistant cells grown in monoculture conditions reproduces this advantage, suggesting that secretion of some factor from resistant cells underlies the effect. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays were used to identify factors secreted by cell lineages. While the less active estrone metabolite was detected in all lineages, the highly active estradiol was only detectable in mono- or coculture with resistant cells. As sensitive cells are more dependent on estrogen signaling than resistant cells, they benefit more from the increase in local estradiol, leading to facilitative growth when cocultured. Cooperative signaling between isogenic cancer cells is enhanced through addition of estradiol and blocked by small molecule inhibitors targeting estrogen signaling pathways. We have developed mathematical models that quantify the strength of competition and facilitation between cell lines and evaluated the effects of treatments that modify these interactions. These analyses support the conclusion that these heterogeneous cell lineages cooperate to survive during therapy through the increased production and sharing of local estradiol. This multidisciplinary approach reveals interactions between ER+ cancer lineages during treatment and provides insight into cell cooperation and competition during treatment, and how these interactions promote cancer cell growth and survival during treatment. Citation Format: Rena Emond, Vince K. Grolmusz, Jason Griffiths, Jinfeng Chen, Frederick R. Adler, Andrea Bild. Clonal facilitation drives estrogen receptor positive (ER+) breast cancer growth and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3133.