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Project 1. Understanding the molecular mechanisms of ageing to improve healthspan and lifespan |
| Ageing is a biological process that affects most living creatures. Despite the scientific advances of the past decades, the mechanisms that lead to ageing in humans are not fully understood. Evidence suggests that accumulation of old (senescent) cells in tissues plays a critical role in the appearance of the symptoms associated with age and age-related diseases. Indeed, it has been shown that if senescent cells are eliminated from tissues in animal models, fitness and longevity increase substantially. Our experiments on senescence will allow us to better understand why we age and also will provide the basis for new treatments that could be applied to slow down and improve age-realted symptoms and diseases. We have identified novel markers of senescence (as shown in the figure), based on the cellular surfaceome, that could be used to detect and target senescent cells in vivo and in vitro. Using nanoparticles and antibodies, we showed that these markers indeed recognize and eliminate senescent cells. Also, we have improved lifespan and delayed age-related decline in mouse models of ageing using drugs to stop senescence. We are interested in defining better markers of ageing and new specific strategies to clear senescent cells from tissues to improve ageing. |
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Recent papers from this project:
Poblocka M, Bassey AL, Smith VM, Falcicchio M, Manso AS,
Althubiti M, Sheng X, Kyle A, Barber R, Frigerio M, Macip S. Targeted
clearance of senescent cells using an antibody-drug conjugate against a
specific membrane marker. Sci Rep. 2021 Oct 13;11(1):20358. doi:
10.1038/s41598-021-99852-2.
Rada M, Qusairy Z, Massip-Salcedo M, Macip S. Kaur A, Macip S, Stover CM. An Appraisal on the Value of Using Nutraceutical Based Senolytics and Senostatics in Aging. Front Cell Dev Biol. 2020 Apr 3;8:218. doi: 10.3389/fcell.2020.00218. eCollection 2020. Ekpenyong-Akiba AE, Poblocka M, Althubiti M,
Rada M, Jurk D, Germano S, Kocsis-Fodor G, Shi Y, Canales JJ, Macip S.
Amelioration of age-related brain function decline by Bruton's tyrosine
kinase inhibition. Aging Cell. 2019 Nov 17:e13079. doi:
10.1111/acel.13079. |
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Project 2. Modulators, effectors and functions of the p53 tumour supressor pathway |
| Apoptosis and senescence have been identified as the two principal mechanisms by which p53 exerts its tumour suppressor capabilities. We and others have shown that the cellular responses to p53 expression can be modulated by a wide range of factors, including reactive oxygen species (ROS), the vitamin A (retinoic acid) pathway and pro-survival signals induced by p53 itself. Thus, identifying new pathways that contribute to p53 functions should help understand its antineoplastic mechanisms and hopefully lead to new therapies. |
| We study the p53 pathway at several levels. We are characterising novel p53 target genes that will
help us to better understand the cellular effects of p53. This is
leading to the identification of new p53 functions beyond its classic
antineoplastic activity. We also investigate how cell fate decisions
after p53 activation can be modulated, with special interest in the
mechanisms involved in senescence (see Project 1) and how p53 functions
can be restored or enhanced in cancer cells, in order to devise better
antineoplastic treatments. Recent papers from this project: Dhokia V, Moss JAY, Macip S, Fox JL. At the Crossroads of Life and Death: The Proteins That Influence Cell Fate Decisions. Cancers (Basel). 2022 May 31;14(11):2745. doi: 10.3390/cancers14112745. Meng X, Cui X, Shao X, Liu Y, Xing Y, Smith V, Xiong S, Macip S, Chen Y. poly(I:C) synergizes with proteasome inhibitors to induce apoptosis in cervical cancer cells. Transl Oncol. 2022 Apr;18:101362. Dhokia V, Macip S. A master of all trades - linking retinoids to different signalling pathways through the multi-purpose receptor STRA6. Cell Death Discov. 2021 Nov 16;7(1):358. d Falcicchio M, Ward JA, Chothia SY, Basran J, Mohindra A, Macip S, Roversi P, Doveston RG. Cooperative stabilisation of 14-3-3σ protein-protein interactions via covalent protein modification. Chem Sci. 2021 Sep 6;12(39):12985-12992. Meng X, Chen Y, Macip S, Leppard K. PML-II regulates ERK and AKT signal activation and IFNα-induced cell death. Cell Commun Signal. 2021 Jul 2;19(1):70. doi: 10.1186/s12964-021-00756-5. Falcicchio M, Ward JA, Chothia SY, Basran J, Mohindra A, Macip S, Roversi P, Doveston RG. Cooperative stabilisation of 14-3-3σ protein–protein interactions via covalent protein modification. Chemical Science 12 (39), 12985-12992, 2021. Falcicchio M, Ward JA, Macip S, Doveston RG. Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer. Cell Death Discov. 2020 Nov 16;6(1):126. Rada M, Vasileva E, Lezina L, Marouco D, Antonov AV, Macip S, Melino G, Barlev NA. Human EHMT2/G9a activates p53 through methylation-independent mechanism 2016 Jul 25. doi: 10.1038/onc.2016.258. Carrera S, Senra J, Acosta MI, Althubiti M, Hammond EM, de Verdier PJ, Macip S. The role of the HIF-1 alpha transcription factor in increased cell division at physiological oxygen tensions. PLoS One. 2014 May 16;9(5):e97938. Carrera S, Cuadrado-Castano S, Samuel J, Jones GD, Villar E, Lee SW, Macip S. Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage. Cell Death Differ. 2013 Jul;20(7):910-9. Masgras I, Carrera S, de Verdier PJ, Brennan P, Majid A, Makhtar W, Tulchinsky E, Jones GD, Roninson IB, Macip S. Reactive oxygen species and mitochondrial sensitivity to oxidative stress determine induction of cancer cell death by p21. J Biol Chem. 2012 Mar 23;287(13):9845-54. Carrera S, de Verdier PJ, Khan Z, Zhao B, Mahale A, Bowman KJ, Zainol M, Jones GD, Lee SW, Aaronson SA, Macip S. Protection of cells in physiological oxygen tensions against DNA damage-induced apoptosis. J Biol Chem. 2010 Mar 12. |
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Project 3. Precision medicines for B-cell leukaemias |
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There is a plethora of new
precision medicines for B-cell malignancy including ‘classical’ kinase
inhibitors, rationally designed inhibitors of anti-apoptotic proteins
and antibody or antibody drug/toxin conjugates with functional
properties. Some are showing spectacular single agent activity in early
phase clinical studies and may reduce or, in combination, even obviate
the need for chemotherapy. Nevertheless, significant problems remain if
these medicines are to be introduced into routine clinical practice in a
rational and affordable manner. Firstly, precision medicines must be
carefully matched in a mechanistic fashion with specific subtypes of
disease. Functional assessment on viable primary malignant cells will be
necessary using assays that faithfully mimic in vivo conditions. A
second challenge is to define mechanism-based synergistic combinations
associated with minimal toxicities rather than simply adding new
precision medicines to existing chemotherapeutic regimens.
We are following these approaches, in collaboration with Prof Martin Dyer's lab, to define novel personalized therapeutic strategies against B-cell malignancies that can be immediately applied in the clinic. For instance, we have recently studied the response of a patient with Hairy Cell Leukaemia to BRAF inhibitor vemurafenib (see figure), both from the clinical perspective and at a cellular and molecular level. |
| Recent papers from this project:
Chen Y, Shao X, Yang H, Ren L, Cui Y, Zhang W, Macip S, Meng X. Interferon gamma regulates a complex pro-survival signal network in chronic lymphocytic leukemia.Eur J Haematol. 2023 Apr;110(4):435-443. doi: 10.1111/ejh.13921. Shao X, Meng X, Yang H, Wang X, Qin L, Shen G, Xi X, Zhao H, Macip S, Chen Y. IFN-γ enhances CLL cell resistance to ABT-199 by regulating MCL-1 and BCL-2 expression via the JAK-STAT3 signaling pathway. .Leuk Lymphoma. 2022 Oct 12:1-8. Smith VM, Lomas O, Constantine D, Palmer L, Schuh AH, Bruce D, Gonchar O, Macip S, Jayne S, Dyer MJS, Eyre TA. Dual dependence on BCL2 and MCL1 in T-cell prolymphocytic leukemia. Blood Adv. 2020 Feb 11;4(3):525-529. doi: 10.1182/bloodadvances.2019000917. Smith VM, Dietz A, Henz K, Bruecher D, Jackson R, Kowald L, van Wijk SJL, Jayne S, Macip S, Fulda S, Dyer MJS, Vogler M. Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma. Haematologica. 2019 Oct 10. pii: haematol.2019.220525. doi: 10.3324/haematol.2019.220525 Chen Y, Peubez C, Smith V, Xiong S, Kocsis-Fodor G, Kennedy B, Wagner S, Balotis C, Jayne S, Dyer MJS, Macip S. CUDC-907 blocks multiple pro-survival signals and abrogates microenvironment protection in CLL. J Cell Mol Med. 2018 Oct 24. doi: 10.1111/jcmm.13935. Chen Y, Peubez C, Jayne S, Kocsis-Fodor G, Dyer MJS, Macip S. Differential activation of pro-survival pathways in response to CD40LG/IL4 stimulation in chronic lymphocytic leukaemia cells. Br J Haematol. 2018 Apr 20. doi: 10.1111/bjh.15197. Chen Y, Germano S, Shelmani G, Kluczna D, Jayne S, Dyer MJS, Macip S. Paradoxical activation of alternative pro-survival pathways determines resistance to MEK inhibitors in chronic lymphocytic leukaemia. Br J Haematol. 2017 Aug 2. doi: 10.1111/bjh.14880. Walter HS, Jayne S, Rule SA, Cartron G, Morschhauser F, Macip S, Karlin L, Jones C, Herbaux C, Quittet P, Shah N, Hutchinson CV, Fegan C, Yang Y, Mitra S, Salles G, Dyer MJ. Long-term follow-up of patients with CLL treated with the selective Bruton's tyrosine kinase inhibitor ONO/GS-4059. Blood. 2017 Apr 4. pii: blood-2017-02-765115. doi: 10.1182/blood-2017-02-765115. Samuel J, Jayne S, Chen Y, Majid A, Wignall A, Wormull T, Najeeb H, Luo J, Jones GD, Macip S, Dyer MJ. Posttranscriptional upregulation of p53 by reactive oxygen species in chronic lymphocytic leukemia.Cancer Res. 2016 Sep 7. pii: canres.0843.2016. Chen Y, Germano S, Clements C, Samuel J, Shelmani G, Jayne S, Dyer MJ, Macip S. Pro-survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia. Br J Haematol. 2016 Jul 29. doi: 10.1111/bjh.14285 Samuel J, Macip S, Dyer MJS. Efficacy of vemurafenib in hairy-cell leukemia. N Engl J Med. 2014 Jan 16;370(3):286-8. Dyer MJS, Vogler M, Samuel J, Jayne S, Wagner S, Pritchard C and Macip S. Precision medicines for B-cell leukaemias and lymphomas; progress and potential pitfalls. Br J Haematol. 2013 Mar;160(6):725-33. |