We aim to understand the molecular mechanisms that control how cells enter and exit the cell cycle, combining microscopy with mathematical modelling to investigate these processes in healthy and cancerous cells.
“Can we stop cancer cells from replicating?”
By adulthood, most cells in the human body have stopped replicating as the body no longer needs to grow. At a cellular level, these cells stop entering the cell cycle – they no longer need to replicate to create more cells. Some of these non-replicating cells are considered to be ‘quiescent’ – they can be stimulated to re-enter the cell cycle and proliferate when needed. This happens when tissues needs to be maintained or repaired. However, controlling this re-entry into the cell cycle is key – if it occurs in the wrong place at the wrong time, proliferating cells can form tumours. Our team is researching exactly how cells are influenced to re-enter the cell cycle at a molecular level, with the aim of working out how to stop cells from continually proliferating out of control. We’re looking to understand how cells signal to each other to get those nearby to start cycling, and how genetic mutations can lead to unchecked tumour cell proliferation. Using CRISPR-engineered cells where we can attach fluorescent molecules to proteins and enzymes involved in the cell cycle, we can see, in real time, what cells do when they decide to re-enter the cell cycle, and how they influence those around them. This gives us incredible insight into these complicated cell processes. If we can understand more about how cells replicate, we can start to develop better targeted therapies that can stop, or kill, cells that start to replicate out of control and become tumorigenic.
“Tight control of cell cycle entry is essential both during normal development and in tissue homeostasis.”
The majority of cells in the adult body are not proliferating and a fraction of these cells are quiescent. Quiescence is a state of reversible cell cycle arrest, from which cells can be stimulated to re-enter the cell cycle. During tissue maintenance and repair, the transition from quiescence to proliferation and proliferation to quiescence must be carefully regulated to maintain tissue size and function. Aberrant regulation of these cell cycle control mechanisms can drive the continuous proliferation of cells, promoting tumorigenesis.
Our aim is to understand how proliferation-quiescence decisions are made at the molecular level in different tissues. We investigate how these systems are controlled in normal human cells, and then determine how mutations and aberrations that occur in tumour cells can drive their continuous proliferation. One approach that we use to interrogate cell cycle control systems is quantitative, live, single-cell imaging of CRISPR-engineered cells. This is a powerful technique that allows us to measure the real-time expression of signalling proteins as cells undergo quiescence-proliferation transitions and thus determine how the coordinated output of this dynamical cell system regulates cellular phenotype.
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Movie of Retinal Pigment Epithelial cells genetically engineered to express mRuby-PCNA, to track cell cycle progression, and p21-GFP, to follow signalling dynamics of this cell cycle inhibitor.
Weston WA, Holt JA, Wiecek AJ, Pilling J, Schiavone LH, Smith DM, Secrier M, & Barr AR. An image-based screen for secreted proteins involved in breast cancer G0 cell cycle arrest (2024). Scientific Data, 11(1). https://doi.org/10.1038/s41597-024-03697-z
Barr AR, Burley A, & Wilkins A. TP53 mutations in urothelial carcinoma: not all one and the same (2024). The Journal of Pathology, 264(2), 125–128. https://doi.org/10.1002/path.6335
Bustraan S, Bennett J, Whilding C, Pennycook BR, Smith D, Barr AR, Read J, Carling D, Pollard A. AMP-activated protein kinase activation suppresses leptin expression indepdently of adipogenesis in primary murine adipocytes (2024). Biochem J. Mar 6;481(5):345-362. Doi: 10.1042/BCJ20240003.
Dragoi CM, Kaur E, Barr AR, Tyson JJ, Novak B. The oscillation of mitotic kinase governs cell cycle latches in mammalian cells (2024). J Cell Sci. Jan 11:jcs.261364. doi: 10.1242/jcs.261364.
Crozier L*, Foy R*, Adib R*, Kar A, Holt JA, Pareri AU, Valverde JM, Rivera R, Weston WA, Wilson R, Regnault C, Whitfield P, Badonyi M, Bennet LG, Vernon EG, Gamble A, Marsh JA, Stable CJ, Saurin A1, Barr AR1, Ly T1. (2023). CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence. Molecular Cell. *Joint first; 1Co-corresponding authors.
Wiggins BG, Wang YF, Burke A, Grunberg N, Vlachaki-Walker J, Dore M, Chahrour C, Pennycook BR, Sanchez-Garrido J, Vernia S, Barr AR, Frankel G, Birdsey GM, Randi AM, Schiering C. (2023). Endothelial sensing of AHR ligands regulates intestinal homeostasis. Nature. 2023 Sep;621(7980):821-829. doi: 10.1038/s41586-023-06508-4.
Wiecek AJ, Cutty SJ, Kornai D, Parreno-Centeno M, Gourmet LE, Malagoli Tagliazucchi G, Jacobson DH, Zhang P, Xiong L, Bond G, Barr AR, Secrier M. (2023). Genomic hallmarks and therapeutic implications of G0 cell cycle arrest in cancer. Genome Biology. May 23; 24(1):128. doi: 10.1186/s13059-023-02963-4.
Hughes FA, Barr AR1, Thomas P1. (2023). Patterns of interdivision time correlations reveal hidden cell cycle factors. Elife. Nov 15;11:e80927. doi: 10.7554/eLife.80927. 1Co-corresponding authors.
Swadling JB1, Warnecke T, Morris KL, Barr AR1 (2022). Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation. Biophysical J. May 25; S0006-3495(22)00417-9. doi: 10.1016/j.bpj.2022.05.024. 1Co-corresponding authors.
Thomsen I, Kunowska N, de Souza R, Moody AM, Crawford G, Wang YF, Khadayate S, Strid J, Karimi MM, Barr AR, Dillon N, Sabbattini P (2021). RUNX1 controls the dynamics of cell cycle entry of naïve resting B-cells by regulating expression of cell cycle and immunomodulatory genes in response to BCR stimulation. Journal of Immunology. Nov 22;207(12):2976-91. doi: 10.4049/jimmunol.2001367
Pennycook BR, Barr AR1 (2021), Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27. Open Biol. Nov 11(11):210125. doi: 10.1098/rsob.210125. 1Corresponding author.
Heldt FS*, Barr AR*, Cooper S, Bakal C, Novak B (2018), A comprehensive model for the proliferation-quiescence decision in response to endogenous DNA damage in human cells. PNAS. Mar 6;115(10):2532-2537. doi: 10.1073/pnas. *Joint first authors
Cooper S, Barr AR, Glen R, Bakal C (2017) Nuclitrack, an integrated nuclei tracking application. Bioinformatics, Jun 20. doi: 10.1093/bioinformatics/btx404.
Asghar US, Barr AR, Cutts R, Beaney M, Babina I, Sampath D, Giltnane J, Arca Lacap J, Crocker L, Young A, Pearson A, Herrera-Abreu MT, Bakal C, Turner NC (2017), Single-cell dynamics determines response to CDK4/6 inhibition in triple negative breast cancer. Clinical Cancer Research, Sep 15;23(18):5561-5572
Barr AR*1, Cooper S*, Heldt FS*, Butera F, Stoy H, Mansfeld J, Novak B, Bakal C1 (2017), DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression. Nature Communications, Mar 20; doi: 10.1038/ncomms14728 *Joint first; 1Co-corresponding authors.
Barr AR, Heldt FS, Zhang T, Bakal C, Novak B (2016), A dynamical framework for the all-or-none G1/S transition. Cell Systems, Jan 27; 2(1):27-37
Barr AR1, Bakal C (2015), A sensitized RNAi screen reveals a ch-TOG genetic interaction network required for spindle assembly. Sci Rep. Jun 3;5:10564. doi: 10.1038/srep10564. 1Corresponding author.