The Origins of Phenotypic Heterogeneity in Cancer.

Heterogeneity is a pervasive feature of cancer, and understanding the sources and regulatory mechanisms underlying heterogeneity could provide key insights to help improve the diagnosis and treatment of cancer. In this review, we discuss the origin of heterogeneity in the phenotype of individual cancer cells. Genotype-phenotype (G-P) maps are widely used in evolutionary biology to represent the complex interactions of genes and the environment that lead to phenotypes that impact fitness. Here, we present the rationale of an extended G-P (eG-P) map with a cone structure in cancer. The eG-P cone is formed by cells that are similar at the genome layer but gradually increase variability in the epigenome, transcriptome, proteome, metabolome, and signalome layers to produce large variability at the phenome layer. Experimental evidence from single-cell-omics analyses supporting the cancer eG-P cone concept is presented, and the impact of epimutations and the interaction of cancer and tumor microenvironmental eG-P cones are integrated with the current understanding of cancer biology. The eG-P cone concept uncovers potential therapeutic strategies to reduce cancer evolution and improve cancer treatment. More methods to study phenotypes in single cells will be the key to better understand cancer cell fitness in tumor biology and therapeutics.

Cancer Cell Fitness Is Dynamic.

Several phenotypes that impact the capacity of cancer cells to survive and proliferate are dynamic. Here we used the number of cells in colonies as an assessment of fitness and devised a novel method called Dynamic Fitness Analysis (DynaFit) to measure the dynamics in fitness over the course of colony formation. DynaFit is based on the variance in growth rate of a population of founder cells compared with the variance in growth rate of colonies with different sizes. DynaFit revealed that cell fitness in cancer cell lines, primary cancer cells, and fibroblasts under unhindered growth conditions is dynamic. Key cellular mechanisms such as ERK signaling and cell-cycle synchronization differed significantly among cells in colonies after 2 to 4 generations and became indistinguishable from randomly sampled cells regarding these features. In the presence of cytotoxic agents, colonies reduced their variance in growth rate when compared with their founder cell, indicating a dynamic nature in the capacity to survive and proliferate in the presence of a drug. This finding was supported by measurable differences in DNA damage and induction of senescence among cells of colonies. The presence of epigenetic modulators during the formation of colonies stabilized their fitness for at least four generations. Collectively, these results support the understanding that cancer cell fitness is dynamic and its modulation is a fundamental aspect to be considered in comprehending cancer cell biology and its response to therapeutic interventions. SIGNIFICANCE: Cancer cell fitness is dynamic over the course of the formation of colonies. This dynamic behavior is mediated by asymmetric mitosis, ERK activity, cell-cycle duration, and DNA repair capacity in the absence or presence of a drug.

Apoptosis induction by 7-chloroquinoline-1,2,3-triazoyl carboxamides in triple negative breast cancer cells.

Breast cancer is a major public health burden in both developed and developing countries and there is still a need to screen new molecules with different modes of actions. The aims of this study were to evaluate the selectivity profile, apoptotic cell death and cell cycle arrest induced by 7-chloroquinoline-1,2,3-triazoyl carboxamides derivatives in hormonal-dependent and hormonal-independent breast cancer cells. Results showed significantly decreased MCF-7 and MDA-MB-231 cells viability in vitro in a dose dependent manner after treatment with 7-chloroquinoline derivatives QTCA-1, QTCA-2 and QTCA-3. QTCA-1 displayed the highest cytotoxic activity from all the tested compounds in MDA-MB-231 with IC50 values of 20.60, 20.42 and 19.91µM in 24, 48 and 72h of treatment respectively. Apoptosis induction was also significantly higher in the hormonal-independent breast cancer cells, with 80.4% of dead cells in MDA-MB-231 and only 16.8% of dead in MCF-7 cells. As a result, G0/G1 cycle arrest was observed in MCF-7 cells and no cell cycle arrest at all was observed in MDA-MB-231 cells. Molecular docking showed a high affinity of QTCA-1 to PARP-1, Scr and PI3K/mTOR targets. These results suggest a strong activity of the 7-chloroquinoline derivative QTCA-1 in independent-hormonal cells and suggest selectivity for triple negative cells.