Ana Cuenda
Group Leader
Research summary
The aim of our group is to understand the role of p38MAPK proteins in physiology and disease. They regulate diverse cellular functions in normal conditions and in response to environmental stress, infection and proinflammatory cytokines. Moreover, they become deregulated in several human disease situations such as oncogenic transformation and inflammation, making them promising targets for new therapeutic avenues.
Publications
Alsina‐Beauchamp D, Escós A, Fajardo P, González‐Romero D, E Díaz‐Mora, Risco A, Martín‐Serrano MA, del Fresno C, Dominguez‐Andrés J, Aparicio N, Zur R, Shpiro N, Brown GD, Ardavín C, Netea MG, Alemany S, Sanz‐Ezquerro JJ, Cuenda A. Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity. EMBO Mol Med 2018; e8485; DOI 10.15252/emmm.201708485.
Risco A, Martin-Serrano MA, Barber DF, Cuenda A. p38γ and p38δ Are Involved in T Lymphocyte Development. Front Immunol. 2018 Jan 29;9:65. doi: 10.3389/fimmu.2018.00065. eCollection 2018.
Cuenda A, Sanz-Ezquerro JJ. p38γ and p38δ: From Spectators to Key Physiological Players. Trends Biochem Sci. 2017; 42(6):431-442
Zur R, Garcia-Ibanez L, Nunez-Buiza A, Aparicio N, Liappas G, Escós A, Risco A, Page A, Saiz-Ladera C, Alsina-Beauchamp D, Montans J, Paramio JM, Cuenda A. Combined deletion of p38γ and p38δ reduces skin inflammation and protects from carcinogenesis. Oncotarget. 2015 May 30;6(15):12920-35
Del Reino P, Alsina-Beauchamp D, Escós A, Cerezo-Guisado MI, Risco A, Aparicio N, Zur R, Fernandez-Estévez M, Collantes E, Montans J, Cuenda A. Pro-oncogenic role of alternative p38 mitogen-activated protein kinases p38γ and p38δ, linking inflammation and cancer in colitis-associated colon cancer. Cancer Res. 2014 Nov 1;74(21):6150-60. doi: 10.1158/0008-5472.CAN-14-0870.
The aim of our research is to determine the physiological and pathological functions of the p38MAPK family in the context of inflammatory diseases and cancer. We hope that our findings will enable us to design new strategies to treat these diseases.
Our laboratory is focused on:
- the study of p38MAPKs as a link between chronic inflammation and cancer, and as mediators of inflammatory diseases, and
- the discovery of new substrates, interacting proteins and inhibitors for these kinases, as a mean to understand their biological and physiological roles.
Inflammation stands at the centre of many pathological (cancer) and natural (tissue repair) processes. It is well known that, in the right place and at the right time, it controls a healthy host response, but uncontrolled inflammation can cause disease. We want to expand our knowledge of the molecular mechanisms involved in the inflammatory response in the settings of: 1) chronic inflammation leading to tumour development (as in colon cancer associated to colitis); 2) infection, and 3) tissue repair/regeneration.
Our studies utilize biochemical, cell biology as well as whole animal model approaches using the genetically modified mice we have generated.
We have discovered that alternative p38MAPK (p38γ and p38δ) play essential roles in the control of the inflammatory response in diverse models of disease and that they are potential targets for the discovery of new drug to treat human pathologies.
In a systemic candidiasis model we have shown that p38γ/p38δ deletion protects against Candida albicans infection and increases mice survival. C. albicans is normally a benign member of the microbiota that colonize the gastrointestinal tract. p38γ/p38δ-/- mice exhibit increased fungicidal activity and decreased systemic inflammation. We also defined a novel Dectin-1 signalling pathway by which p38γ and p38δ are essential for ERK pathway activation and contribute to production of inflammatory cytokines in macrophages infected by C. albicans. We demonstrated that genetic and chemical inhibition of p38γ/p38δ reduce mice fungal burden, establishing p38γ/p38δ as therapeutic targets in humans.
In the collagen-induced arthritis model of chronic inflammation, we showed that combined p38γ and p38δ deficiency markedly reduced synovial inflammation and bone destruction. Reduced arthritis severity in p38γ/δ-null mice was associated with lower cytokine production, T cell proliferation and anti-collagen antibody responses than in controls, indicating that p38γ and p38δ are crucial regulators of inflammatory joint destruction in CIA. We proposed p38γ and p38δ as potential therapeutic targets in complex diseases, such as rheumatoid arthritis, that involve innate and adaptive immune responses.
Chronic inflammation is a known risk factor for tumourigenesis. We analysed the role of p38γ and p38δ in skin cancer and in colitis-associated colon cancer (CAC). We found that p38γ/δ deficiency decreased tumour formation significantly in both models, in parallel with decreased production of proinflammatory cytokines and chemokines. In the case of CAC, analysis of leukocyte populations in p38γ/δ-null mouse colon showed less macrophage and neutrophil recruitment than in WT mice. The generation of chimeric mice by bone marrow transplantation determined that p38γ/p38δ in the hematopoietic compartment control tumour development in the colon. Our results establish that p38γ and p38δ are central to colon inflammation-induced tumour formation, and validate these p38MAPKs as potential targets for cancer therapy.
