Overview. Research in the lab focuses on cellular and molecular mechanisms underlying cell and tissue aging, with emphasis on epigenetics and age-associated epigenetic changes that predispose to cancer. We are also interested in developing epigenetic therapies
Untitled to combat cancer, and ultimately epigenetic chemopreventative strategies. We employ in vitro
models, mouse models, human tissues and state-of-the-art analyses of large epigenomics and single cell sequencing datasets. We do collaborative, multidisciplinary research.

Why does the incidence of cancer increase with age? While we are fundamentally interested in basic mechanisms of cell and tissue aging, we are keen to understand how aging predisposes to disease. The incidence of many cancers increases with age. Indeed, age is the biggest single risk factor for many cancers. However, the reason for this is poorly understood (link to Cancer and Aging). We believe that a substantial reduction in the incidence and deaths from cancer will ultimately come from a better understanding of cancer as a disease of aging, thereby facilitating risk assessment, early detection and chemoprevention.


Figure : A model for age-associated increase in cancer incidence . Open lollipops, unmethylated CpG; filled lollipop, methylated CpG; yellow lightning bolt, genotoxic/mutagenic event.

Evidence suggests that multiple factors conspire to drive age-associated cancer (see Figure above). Some congenital cancer-causing mutations are thought to be well-tolerated by young cells and tissues (e.g. mutant gene B). Other cancer-causing mutations are acquired through aging (e.g. mutant gene A). These congenital and acquired mutations conspire with other more progressive events, telomere shortening, replication stress, epigenetic and metabolic changes, to drive a dramatic increase in late-life cancer. In the Adams lab, we are interested in defining the mechanistic causes and consequences of age-associated epigenetic changes, particularly those events that pre-dispose to cancer. A long-term goal of the lab is to develop epigenetic-based therapies that can prevent age-associated events that predispose to cancer, with a view to cancer chemoprevention.

See: Adams, P.D., Jasper, H., Rudolph, K.L., Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer. Cell Stem Cell, 2015 Jun 4;16(6):601-612. doi: 10.1016/j.stem.2015.05.002. PMID: 26046760

Cellular Senescence. While research in the lab is increasingly moving towards mouse models of cancer and aging, our interest in the relationship between cancer and aging initiated in our studies of cell senescence.

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” or Senescence Associated Secretory Phenotype (SASP)) 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 and also likely due to the chronic tissue damaging effects of the SASP. In sum, cell senescence has both beneficial (healing) and detrimental (hurting) effects for a multicellular organism.

See: Adams, P.D. Healing and hurting: molecular mechanisms, functions and pathologies of cellular senescence. Molecular Cell. 36: 1-14, 2009.

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.

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.

To initiate studies in this area, we have analyzed the HIRA histone chaperone complex. This complex, comprised of HIRA, UBN1 and CABIN1, collaborates with histone-binding protein ASF1a to incorporate histone variant H3.3 into chromatin in a DNA replication-independent manner. Consistent with this role in DNA replication-indpendent chromatin metabolism, we have previously implicated this chaperone in regulation of chromatin in non-proliferating cells. To better understand HIRA’s function and mechanism, we integrated HIRA, UBN1, ASF1a and histone H3.3 ChIP-seq and gene expression analyses. Most HIRA-binding sites co-localize with UBN1, ASF1a and H3.3 at active promoters and active and weak/poised enhancers. At promoters, binding of HIRA/UBN1/ASF1a correlates with the level of gene expression. HIRA is required for deposition of histone H3.3 at its binding sites. There are marked differences in nucleosome and co-regulator composition at different classes of HIRA-bound regulatory site. Underscoring this, we report novel physical interactions between the HIRA complex and transcription factors, a chromatin insulator and an ATP-dependent chromatin-remodelling complex. Our results map the distribution of the HIRA chaperone across the chromatin landscape and point to different interacting partners at functionally distinct regulatory sites.

See: Pchelintsev, N.A., McBryan, T., Rai, T.S., van Tuyn, J., Ray-Gallet, D., Almouzni, G.A., Adams, P.D. Placing the HIRA histone chaperone complex in the chromatin landscape. Cell Reports, April 18, 2013.

These studies are being extended to an analysis of HIRA, histone H3.3 and other chromatin features in senescent cells. Recent studies have shown that HIRA controls a dynamic chromatin landscape in senescent cells and this is required for efficient senescence-associated tumor suppression.

Rai, T.S., Cole, J.C., Nelson, D.M., Dikovskaya, D., McBryan, T., Faller, W., van Tuyn, J., Morrice, N., Hewitt, R.N., Manoharan, I., Pchelintsev, N.A., Ivanov, A., Brock, C., Drotar, M.E., Nixon, C., Clark, W., Sansom, O.J., King, A., Blyth, K., Adams, P.D. HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Genes Dev. 2014, 28:2712-25. doi: 10.1101/gad.247528.114.

We have performed ChIP-seq and DNA methyl-seq of several histone modifications and DNA methylation in proliferating and senescent cells. These studies have revealed remarkable and paradoxical insights into chromatin in senescence, and the role of senescence as a tumor suppressor and its contribution to tissue aging. Mechanistic hypotheses are being tested, and these analyses are being extended to studies of human and mouse aged and pre-malignant tissues to define the mechanism by which age-associated chromatin changes predispose to cancer.

See: Shah, P.P., Donahue, G., Nelson, D.M., Cruickshanks, H., McBryan, T., Cao, K., Aggarwala, V., Adams, P.D.*, Berger, S.L.* Lamin B1 Depletion in Senescent Cells Leads to Large-Scale Changes in the Chromatin Landscape. Genes and Development. 2013 Aug 15;27(16):1787-99. doi: 10.1101/gad.223834.113. Epub 2013 Aug 9. *Corresponding authors.

Senescent cells appear “epigenetically primed” to form cancer cells. Altered DNA methylation and associated destabilization of genome integrity and function is a hallmark of cancer. Replicative senescence is a tumour suppressor process that imposes a limit on the proliferative potential of normal cells that all cancer cells must bypass. Here we show by whole-genome single-nucleotide bisulfite sequencing that replicative senescent human cells exhibit widespread DNA hypomethylation and focal hypermethylation. Hypomethylation occurs preferentially at gene-poor, late-replicating, lamin-associated domains and is linked to mislocalization of the maintenance DNA methyltransferase (DNMT1) in cells approaching senescence. Low-level gains of methylation are enriched in CpG islands, including at genes whose methylation and silencing is thought to promote cancer. Gains and losses of methylation in replicative senescence are thus qualitatively similar to those in cancer, and this ‘reprogrammed’ methylation landscape is largely retained when cells bypass senescence. Consequently, the DNA methylome of senescent cells might promote malignancy, if these cells escape the proliferative barrier. Since senescent cells appear to be imperfect tumor suppressors, at least from an epigenetic perspective, accumulation of senescent cells in aged tissues might contribute to increased incidence of cancer with age.

Cruickshanks, H., McBryan, T., Nelson, D.M., VanderKraats, N.D., Shah, P., van Tuyn, J., Rai, T.S., Brock, C., Donahue, G., Dunican, D.S., Drotar, M.E., Meehan, R.R., Edwards, J.R., Berger, S. L., and Adams, P.D.  Senescent cells harbor features of the cancer epigenome. Nat. Cell Biol. 2013 Nov 24. doi: 10.1038/ncb2879.


DNA methylation gains and losses in senescent cells overlap with hyper and hypomethylation in cancer. Paradoxically, this suggests that the epigenome of senescent cells might be primed for progression to cancer. In turn, this suggests that senescence might be an imperfect tumor suppressor mechanism, and accumulation of senescent cells with age might predispose to cancer. The reason(s) why cancer increases with age in humans is poorly understood, at present. See Cruickshanks et al, 2013 for details.

Histone metabolism in senescent cells. Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. We have shown that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C-negative, but strongly gammaH2AX- and H3K27me3-positive, cytoplasmic chromatin fragments (CCF) bud off nuclei, and this is associated with lamin B1 downregulation and the loss of nuclear envelope integrity. In the cytoplasm, CCF are targeted by the autophagy machinery. Senescent cells exhibit markers of lysosomal-mediated proteolytic processing of histones and are progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlates with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression.

See: Ivanov, A., Pawlikowski, J., Manoharan, I., Rai, T. S., Nelson, D. M., Shah, P. P., Drotar, M., Wu, H., Berger, S. L., and Adams, P. D. Lysosome-dependent processing of histones in senescent cells. J. Cell Biol. 2013 Jul 8;202(1):129-43. doi: 10.1083/jcb.201212110. Epub 2013 Jul 1.


Histone H3 loss associated with nevus maturation (in deeper/lower portion of nevus).

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.

See: Kennedy, A.L., Morton, J.P., Jamieson, N.B., Manoharan, I., Nelson, D.M. Jamieson, N.B., Pawlikowski, J.S., McBryan, T., Doyle, B., McKay, C., Oien, K.A., Enders, G.H., Zhang, R., Sansom, O.J., Adams, P.D. Activation of the PIK3CA/AKT pathway suppresses senescence induced by an activated RAS oncogene to promote tumorigenesis. Mol. Cell., 42: 36-49, 2011.

Wnt signalling stimulates nevogenesis. Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (Senescence Associated Secretory Pathway (SASP)). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and SASP are thought to contribute. Melanocytes within benign human nevi are a paradigm for tumor suppressive senescent cells in a pre-malignant neoplasm. We performed a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA-seq. This analysis emphasized the importance of senescence-associated proliferation arrest in suppression of transformation. Previous studies showed that activated Wnt-signaling can delay or bypass senescence. Consistent with this, we present evidence that repression of proliferation-promoting Wnt target genes contributes to melanocyte senescence in vitro. Surprisingly, these same genes are expressed in some senescent human melanocytes in nevi, and this is linked to histological indicators of higher proliferative and malignant potential. In a mouse, activated Wnt-signaling delays senescence-associated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt-signaling can potentiate nevogenesis in vivo by delaying senescence.  Further, we suggest that activated Wnt-signaling in human nevi undermines senescence-mediated tumor suppression and enhances the probability of malignancy.

See: Pawlikowski J.S., McBryan T., van Tuyn J., Drotar M.E., Hewitt R.N, Maier A.B., King A., Blyth K., Wu H., Adams P.D. Wnt signaling potentiates nevogenesis. Proc. Natl. Acad. Sci. 2013 Sep 16. [Epub ahead of print], PMID: 24043806


A model for formation of human benign nevi.

More recently, we extended this model to propose that activated Wnt signaling caused by germline variants in the Wnt pathway cooperate with post-zygotic mutation of N-RAS to drive pathological nevogenesis in the form of congenital melanocytic nevus (CMN) syndrome. Importantly, features of CMN syndrome were suppressed by acute post-natal treatment of mice with a MEK inhibitor to block activated RAS signalling.

Pawlikowski, J.S., Brock, C., Chanudet, E., Paine, S., Nixo, C., McGregor, F., Lambie, W., Holmes, W., Mullin, J., Wu, H., Blyth, K., King, A., Kinsler, V.A, Adams, P.D. Acute inhibition of MEK suppresses congenital melanocytic nevus syndrome in a novel murine model driven by activated NRAS and Wnt. J. Invest. Derm., 2015 Mar 27. doi: 10.1038/jid.2015.114. [Epub ahead of print] PMID: 25815427



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