Research
Cell senescence is an irreversible proliferation arrest instigated by a variety of molecular triggers including acquisition of activated oncogenes, and shortened telomeres caused by excess rounds of cell division. In addition, senescent cells secrete a cocktail of inflammatory cytokines, chemokines and matrix proteases (the “inflammatory secretome”) that is capable of influencing behavior of neighboring cells, including immune cells. Compelling evidence now indicates that cell senescence is a potent tumor suppression mechanism, notably in cells harboring activated oncogenes. Senescence-associated proliferation arrest and the inflammatory secretome act in concert to achieve tumor suppression: proliferation arrest directly curtails tumor growth and the inflammatory secretome calls on innate immune cells to eliminate the offending damaged cells. Because of senescence, most primary human cells have a finite proliferative lifespan, and evidence has been presented that senescence contributes to tissue ageing in vivo, in part by limiting the proper self-renewal of stem cells and tissues. In sum, cell senescence has both beneficial (healing) and detrimental (hurting) effects for a multicellular organism.
Senescent cells are often characterised by domains of facultative heterochromatin, called senescence-associated heterochromatin foci (SAHF), which are thought to repress expression of proliferation-promoting genes. Interestingly, both aging and cancer are also accompanied by marked changes in chromatin structure. We are interested in the epigenetic changes associated with senescence, and their contribution to the senescent phenotype. In addition, since senescent cells are thought to accumulate with age, we are testing the hypothesis that senescence-associated changes in chromatin structure contribute to age-associated changes in chromatin structure, and onset of diseases of aging, including cancer.
Not all oncogenes are equal – a basis for oncogene cooperation. Given the important role of senescence in tumor suppression, it is important to understand how the genetic alterations commonly found in human cancers interact to overcome the senescence barrier to tumorigenesis. Mutations in both RAS and the PTEN/PIK3CA/AKT signaling module are found in the same human tumors. PIK3CA and AKT are downstream effectors of RAS, and the selective advantage conferred by mutation of two genes in the same pathway is unclear. Based on a comparative molecular analysis, we have shown that activated PIK3CA/AKT is a weaker inducer of senescence than is activated RAS. Moreover, concurrent activation of RAS and PIK3CA/AKT impairs RAS-induced senescence. In vivo, bypass of RAS-induced senescence by activated PIK3CA/AKT correlates with accelerated tumorigenesis. Thus, not all oncogenes are equally potent inducers of senescence and, paradoxically, a weak inducer of senescence (PIK3CA/AKT) can be dominant over a strong inducer of senescence (RAS). For tumor growth, one selective advantage of concurrent mutation of RAS and PTEN/PIK3CA/AKT is suppression of RAS-induced senescence. In tumors haboring activated RAS and inactivation of PTEN, inhibition of a downstream effector of the PIK3CA/AKT pathway, mTOR, restores cell senescence. Thus, our new understanding of interaction between the RAS and PIK3CA/AKT pathways might be exploited in rational development and targeted application of pro-senescence cancer therapies.
Genome-wide analysis of chromatin structure and chromatin regulators in senescent cells.
To better understand the structure and function of chromatin in senescent cells, we are performing genome-wide analyses of histone modifications and DNA methylation to compare chromatin in proliferating and senescent cells. To do this, we are using next generation sequencing (ChIP-seq), microarray and proteomic approaches and whole genome single nucleotide bisulphite modified DNA sequencing. To complement this analysis of epigenetic marks in senescence, we are also exploring the genome-wide distribution of histone chaperones in senescent cells, again using state-of-the-art approaches. We have also collected gene expression data to build a comprehensive, integrated view of the epigenetic control of senescent cell function.
Histone metabolism in senescent cells.
Recent studies by our lab and published by others have shown that, remarkably, total histone content declines in senescent cells. We are investigating the mechanism underlying this decrease in histone content and its functional consequences.
Investigation of the senescence secretome.
Senescent cells secrete a number of matrix metalloproteases (MMPs), best known for their ability to degrade extracellular matrix. Using in vitro and in vivo approaches, we are investigating the impact of these MMPs on senescence-mediated tumor suppression.
