Cellular senescence in cancer and ageing
Senescence is a state of persistent cell cycle arrest triggered by various stimuli but they are not inert. They actively communicate with their surroundings, shaping the tissue microenvironment and potentially burdening the individuals. We are particularly interested in understanding what senescent cells do to tissues and how they achieve such altered functionality.
High-order chromatin organisation
Senescence-associated genes are often lineage-specific genes, which are tightly controlled through the epigenetics mechanism. Lineage- or cell-type-specific genes define cellular functionality (represented by senescence-associated secretory phenotype, SASP). Thus, senescence can be viewed as a gain-of-function phenotype. Indeed, SASP genes can be induced through extensive 3D rewiring of the enhancer-promoter network (Olan et al. Nat Commun 2020).
Senescence is often accompanied by global chromatin reorganisation, represented by senescence-associated heterochromatin foci (SAHFs) (Narita et al. Cell 2003). SAHF-formation is associated with upregulation of HMGA1 (Narita et al. Cell 2006) and loss of Lamin B1 (Sadaie et al. Genes Dev 2013). During SAHF-formation, chromatin is organised into concentric epigenetic layers with H3K9m3-core with H3K27me-shell, excluding euchromatin regions (Chandra et al. Mol Cell 2012).
Thus, we suspect that the process is important not only for heterochromatin formation but also for separating active regions from the repressive environment. This notion is supported by our recent data, desilencing of ‘lineage-inappropriate’ genes from H3K9me3 heterochromatin primarily at peri-SAHF regions (Tomimatsu et al. Nat Aging 2022).
We are asking to what extent we can generalise the SAHF-like organisation and its impact on gene regulation. See our recent review article on this topic (Olan and Narita. Annu. Rev. Cell Dev. Biol. 2022)
Functions of senescent cells
Non-cell-autonomous activities are not just SASP. We have shown that NOTCH-mediated direct cell contact can locally propagate senescence phenotype (‘lateral induction’ of senescence) (Hoare et al. Nat Cell Biol. 2016). This study also defined distinct SASP waves, highlighting the temporospatial heterogeneity of senescence. The same juxtacrine mechanism modulates the global chromatin landscape (Parry et al. Nat Commun 2018), proposing a concept, ‘non-cell-autonomous epigenetic regulation.
Using the mouse liver oncogene-induced senescence (OIS) model, where we can assess senescence functionality (senescent cells provoke immune interaction), we have identified new effector mechanisms for the SASP (Gonçalves et al. Cell Rep. 2021) and the subsequent immune-mediated senescence elimination (Yin et al. Genes Dev. 2022). We are further studying the dynamic and functional interaction between OIS cells and immune cells and how it impacts tumorigenesis in vivo. See also our review articles on OIS (e.g. Chan and Narita. Gens Dev. 2019).
Age-associated spontaneous cancer mouse model
We have shown the functional relevance of autophagy in senescence (Young, Narita et al. Genes Dev 2009, Narita, Young et al. Science 2011). To further extend these in vitro studies, we have generated new autophagy mouse models, where we can switch on/off autophagy using Doxycycline (Dox) -inducible sh-Atg5 (Cassidy, Young, Pérez-Mancera et al. Autophagy 2018). They are hypomorphic and also allow for temporospatial regulation of autophagy without any confounding effects on development. We genetically validated the long-standing question in mammals: does the autophagy-decline induces premature ageing? Moreover, restoration of autophagy leads to a dramatic age reversal but increased tumorigenesis (Cassidy et al. Nat Commun 2020), providing a platform for investigating age-associated tumorigenesis. See our recent review article on this topic (Cassidy and Narita. Mol. Oncol. 2022)