Genomic approaches to cell cycle and cancer
Because uncontrolled cell division is so dangerous for an organism, cells must know not only when to divide, but—crucially—when not to. The ability of cells to chose not to divide prevents tumors and allows tissue to adopt their proper form. Many cell in our bodies must also retain the ability to divide again when signaled, e.g., when the organism must grow, or a damaged tissue must be repaired. A cell in a temporary, non-dividing state is “quiescent.” Quiescence is a common state for many somatic cells, including fibroblasts, lymphocytes, hematopoietic stem cells, and even dormant tumor cells. Failure to appropriately regulate the transition between quiescence and proliferation underlies several common and lethal disorders, such as cancer, fibrosis and autoimmune diseases. Yet, despite its prevalence and medical importance, and in stark contrast to our detailed understanding of cell proliferation, we know remarkably little about quiescence. Research in the Coller lab focuses on understanding the molecular basis of quiescence.
Our lab’s research has shown that quiescence isn’t a “sleepy” or default state. In contrast, we found that that quiescence is an active and highly regulated process. We have used sophisticated technologies and computational approaches for understanding the cellular networks that underlie quiescence. We have applied microarrays, mass spectrometry-metabolomics, mass spectrometry-epigenetics and high throughput microRNA profiling to generate and analyze high quality datasets defining the characteristics of proliferating and quiescent cells. We have coupled these high-throughput approaches with cell biological, genetic and biochemical strategies to elucidate the functional importance of our findings. In addition, we have established mouse models of injury and tumorigenesis to evaluate our results in the context of normal physiology and pathology.
Through these approaches, in a model system involving primary human diploid fibroblasts, our laboratory’s research has revealed changes in the expression of genes, metabolites, microRNAs and histone modifications when cells transition between proliferation and quiescence. We discovered that quiescent cells activate the notch signaling pathway, and that it actively protects them from irreversible cell cycle states such as differentiation and senescence. We further showed that human tumors employ the same pathway to evade terminal differentiation and irreversible cell cycle arrest. We discovered that cell cycle arrest with quiescence is not a default state, but rather, is actively maintained by microRNAs and histone modifications that enforce cell cycle exit. We also discovered that non-dividing, but not proliferating, fibroblasts actively engage the pentose phosphate pathway to protect themselves from and apoptosis.