Abstract IA09: The dynamics of cancer cell heterogeneity

Abstract

Abstract Cancer cells behave heterogeneously regarding proliferation and survival to therapy. This heterogeneity is not static, fluctuating over time with different frequencies and amplitudes. Here we set out to measure the dynamics of the proliferative and tolerant phenotype of untreated and glioma cell lines treated with temozolomide (TMZ) and/or cisplatin. For this, we followed single clones of glioma cells and measured the number of cells in each clone for three consecutive time points. The larger the clone, the more similar is their proliferation rate among clones of the same size, indicating that division shuffled the proliferation phenotypes of the cells. The response to TMZ or cisplatin is highly variable in small clones, but this response becomes more homogeneous with the increase in colony size, due to small heritability of the phenotype that controls the response to these drugs. The reduction in variance in relation to colony size is twice as high for the response to TMZ or cisplatin when compared to untreated colonies. Inhibition of HDAC prior to treatment freezes the variability of the response to TMZ, but not cisplatin, so that small and large colonies respond with the same variance. This indicates that the response to TMZ is phenocopied over generations of cells in the presence of HDAC inhibition, but rapidly fluctuates in its absence. With the aid of a computational model of the mother-daughter and sister-sister differences in proliferation and survival in the presence of the chemotherapeutic drugs, we described the dynamics of these phenotypes in response to TMZ, cisplatin, and their combination. We conclude that the proliferative and response to chemotherapeutic phenotypes fluctuate with time and can be stabilized with inhibition of HDACs, with important insights into drug combination to improve therapeutic potential. Citation Format: Guido Lenz, Giovana R. Onzi, Luiza C. Pereira, Karen Breitenbach, Luana s. Lenz, Brunnet G. Leonardo, Eloisa Dalsin. The dynamics of cancer cell heterogeneity [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA09.