João Barata Lab

Signaling in Cancer

We aim to establish a dynamic research vector on different facets of cancer biology. Our main emphasis has been on hematological malignancies and especially T-cell acute lymphoblastic leukemia (T-ALL). Because we want to understand the mechanisms by which malignant T-cells acquire a selective advantage over their healthy counterparts, we are also interested in studying particular features of normal T-cell biology (e.g. how developing thymocytes respond to certain extracellular cues, most notably interleukin 7).

In order to understand whether the oncogenic mechanisms we identify in T-ALL extend to other cancers, we study other leukemias, especially B-cell ALL. Finally, we recently initiated new research avenues on brain tumors and on lung cancer.

Overall, our research aims to illuminate the role that cell-intrinsic aberrations and microenvironmental factors might play during tumor initiation and progression, metastization, and response to treatment. Our goal is to characterize the cellular and molecular mechanisms underpinning these processes, identifying genes and signaling pathways that are implicated in cancer maintenance and expansion at different stages.

To do so, we make use of patient material, as a key source of insights into the disease, and integrate different biochemical, cellular and molecular biology techniques with appropriate in vitro and in vivo models - enabling an overall appreciation of the molecular, cellular and systemic nuances associated with cancer. Ultimately, our research seeks to identify and characterize crucial biomarkers and molecular targets for the development of novel, more selective therapies against cancer. Our ultimate goal is to go all the way from fundamental discoveries to the development of novel therapeutic strategies.

Some of our current research lines and technology transfer efforts include:

1) The in-depth characterization of IL-7/IL-7R signaling and how it contributes to the development of leukemia and other cancers.

2) The analysis of the mechanisms by which CK2 and PTEN/PI3K signaling interaction modulates T-ALL.

3) The applied development and exploitation of new therapies against T-ALL (responsible: Rita Fragoso).

4) The identification of key molecular determinants of metastasis to the brain (responsible: Cláudia Faria).

Research Team

Research Areas

• Cancer biology
• Signal transduction
• Cellular and molecular biology
• Rational targeted therapies

Ongoing Research Projects

2021/2024 IL7R in lung cancer development, metastasis and resistance to immune checkpoint inhibitor therapy. Coordinator: João Barata. Funding Agency: la Caixa Foundation.

2020/2021 Antibody-based IL-7R targeted therapies. Coordinator: João Barata. Funding Agency: European Commission.

2018/2021 Descodificar a interação entre CK2, PI3K, e o relógio molecular circadiano para melhor compreender a biologia e maximizar respostas terepêuticas dirigidas contra leucemia de células T. Coordinator: João Barata. Funding Agency: Fundação para a Ciência e a Tecnologia.

2018/2021 Uso da genómica para a identificação de novas terapias alvo nas metástases cerebrais. Coordinator: Cláudia Faria. Funding Agency: Fundação para a Ciência e a Tecnologia.

Awards

Major Awards:

2021 Pfizer Award in Basic Research - Sociedade das Ciências Médicas de Lisboa

2016 D. Manuel de Mello Award (awarded to C. Faria)

2014 Pfizer Award in Clinical Research - Sociedade das Ciências Médicas de Lisboa

2013 Silver Medal for Distinct Services from the Portuguese Ministry of Health. (awarded to J.T. Barata)

2012 Best Immunology Paper Award. Portuguese Society of Imunology (SPI).

2011 Pfizer Award in Clinical Research - Sociedade de Ciências Médicas de Lisboa

2009 Pulido Valente Science Prize in Translational Molecular Oncology (awarded to A. Silva)

2008 Pfizer Award in Basic Research - Sociedade de Ciências Médicas de Lisboa

Selected Publications

A. Almeida, J.L. Neto, A. Cachucho, M. Euzébio, X. Meng, R. Kim, M.B. Fernandes, B. Raposo, M.L. Oliveira, D. Ribeiro, R. Fragoso, P.P. Zenatti, T. Soares, M.R. de Matos, J. Ronchi Corrêa, M. Duque, K.G. Roberts, Z. Gu, C. Qu, S. Pyne, N.J. Pyne, V.M. Barreto, I. Bernard-Pierrot, E. Clappier, C.G. Mullighan, A.R. Grosso, J.A. Yunes*, J.T. Barata* (2021). Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia. Nature Communications. *co-corresponding authors

A. Silva*, A. Almeida*, A. Cachucho#, J.L. Neto#, S. Demeyer, M. Matos, T. Hogan, Y. Li, J. Meijerink, J. Cools, A.R. Grosso, B. Seddon**, J.T. Barata** (2021). Overexpression of wild type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma. Blood 138 (12): 1040-1052. *co-first authors; #co-second authors; ** co-corresponding authors

I. Pinto, M. Duque, J. Gonçalves, P. Akkapeddi, M.L. Oliveira, R. Cabrita, J.A. Yunes, S.K. Durum, J.T. Barata, R. Fragoso (2020). NRARP displays either pro- or anti-tumoral roles in T-cell acute lymphoblastic leukemia depending on Notch and Wnt signaling. Oncogene 39(5):975-986.

J.T. Barata, S.K. Durum, B. Seddon (2019). Flip the coin: IL-7 and IL-7R in health and disease. Nature Immunology 20 (12): 1584-1593.

P. Akkapeddi, R. Fragoso, J.A. Hixon, A.S. Ramalho, M.L. Oliveira, T. Carvalho, A. Gloger, M. Matasci, F. Corzana, S.K. Durum, D. Neri, G.J.L. Bernardes*, J.T. Barata* (2019). A fully human anti-IL-7Rα antibody promotes antitumor activity against T-cell acute lymphoblastic leukemia. Leukemia. 33 (9): 2155-2168. * co-corresponding authors

S.T. Ribeiro, M. Tesio, J.C. Ribot, E. Macintyre, J.T. Barata, B. Silva-Santos (2017). Casein Kinase 2 controls the survival of normal thymic and leukemic γδ T-cells via promotion of AKT signaling. Leukemia 31 (7): 1603-1610.

A. Melão, M. Spit, B.A. Cardoso, J.T. Barata (2016). Optimal IL-7R-mediated signaling, cell cycle progression and viability of T-cell acute lymphoblastic leukemia cells rely on CK2 activity. Haematologica 101 (11): 1368-1379.

N.C. Correia, R. Fragoso, T. Carvalho, F.J. Enguita, J.T. Barata (2016). MiR-146b negatively regulates migration and delays progression of T-cell acute lymphoblastic leukemia. Scientific Reports 23 (6): 31894.

L.M. Sarmento, V. Póvoa, R. Nascimento, G. Real, I. Antunes, L.R. Martins, C. Moita, P.M. Alves, M. Abecasis, L.F. Moita, R.M.E. Parkhouse, J.P.P. Meijerink, J.T. Barata (2015). CHK1 overexpression in T-cell acute lymphoblastic leukemia is essential for proliferation and survival by preventing excessive replication stress. Oncogene 34(23): 2978-2990.

R. Pulido, S.J. Baker, J.T. Barata, (...), N.R. Leslie (2014). A unified nomenclature and amino acid numbering for human PTEN. Science Signaling 7 (332), pe15.

R.D. Mendes*, L.M. Sarmento*, K. Canté-Barrett, L. Zuurbier, J. Buijs-Gladdines, V. Povoa, W.K. Smits, M. Abecassis, J.A. Yunes, E. Sonneveld, M.A. Horstmann, R. Pieters, J.T. Barata**, and J.P.P. Meijerink** (2014). PTEN micro-deletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events. Blood 2014 124(4):567-78. *co-first authors; ** co-senior authors

A. Lonetti*, I.L. Antunes*, F. Chiarini, E. Orsini, F. Buontempo, F. Ricci, P.L. Tazzari, P. Pagliaro, F. Melchionda, A. Pession, A. Bertaina, F. Locatelli, J.A. McCubrey, J.T.Barata**, A.M. Martelli** (2014). Activity of the pan-class I phosphoinositide 3-kinase inhibitor NVP-BKM120 in T-cell acute lymphoblastic leukemia. Leukemia 28 (6): 1196–1206. *co-first authors; ** co-senior authors

L.R. Martins, P. Lúcio, A. Melão, I. Antunes, B.A. Cardoso, R. Stansfield, M.T. Bertilaccio, P. Ghia, D. Drygin, M.G. Silva, J.T. Barata (2014). Activity of the clinical-stage CK2-specific inhibitor CX-4945 against chronic lymphocytic leukemia. Leukemia 28 (1): 179–182.

J.T. Barata (2013). IL-7Rα: Mr Hyde's twists and turns. Blood 122 (26): 4151-4152.

N. Correia, K. Durinck, A.P. Leite, M. Ongenaert, P. Rondou, F. Speleman, F.J. Enguita, J.T. Barata (2013). Novel TAL1 targets beyond protein-coding genes: identification of TAL1-regulated microRNAs in T-cell acute lymphoblastic leukemia. Leukemia 27 (7): 1603-1606.

P.P. Zenatti, D. Ribeiro, W. Li, L. Zuurbier, M.C. Silva, M. Paganin, J. Tritapoe, J.A. Hixon, A.B. Silveira, B.A. Cardoso, L.M. Sarmento, N. Correia, M. L. Toribio, J. Kobarg, M. Horstmann, R. Pieters, S.R. Brandalise, A.A. Ferrando, J.P. Meijerink, S.K. Durum, J.A. Yunes, J.T. Barata (2011). Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nature Genetics 43 (10): 932-939.

B.A. Cardoso, S.F. de Almeida, A.B. Laranjeira, M. Carmo-Fonseca, J.A. Yunes, P.J. Coffer, J.T. Barata (2011). TAL1/SCL is downregulated upon histone deacetylase inhibition in T-cell acute lymphoblastic leukemia cells. Leukemia 25 (10): 1578-1586.

A. Silva, A.B. Laranjeira, L.R. Martins, B.A. Cardoso, J. Demengeot, J.A. Yunes, B. Seddon, J.T. Barata (2011). IL-7 contributes to the progression of human T-cell acute lymphoblastic leukemias. Cancer Research 71 (14): 4780-4789.

A. Silva, A. Gírio, I. Cebola, C.I. Santos, F. Antunes, J.T. Barata (2011). Intracellular reactive oxygen species are essential for PI3K/Akt/mTOR-dependent IL-7-mediated viability of T-cell acute lymphoblastic leukemia cells. Leukemia 25 (6): 960-967.

L.R. Martins, P. Lúcio, M.C. Silva, P. Gameiro, M.G. Silva, J.T. Barata (2010). Targeting CK2 Overexpression and Hyperactivation as a Novel Therapeutic Tool in Chronic Lymphocytic Leukemia. Blood 116 (15):2724-2731

C.M. Henriques, J. Rino, R.J. Nibbs, G.G. Graham, J.T. Barata (2010). IL-7 induces rapid clathrin-mediated internalization and JAK3-dependent degradation of IL-7Rα in T cells. Blood 115 (16): 3269-3277.

P.Y. Jotta, M.A. Ganazza, A. Silva, M.B. Viana, M.J. da Silva, L.J.G. Zambaldi, J.T. Barata, S.R. Brandalise, J.A. Yunes (2010). Negative prognostic impact of PTEN mutation in pediatric T-cell acute lymphoblastic leukemia. Leukemia 24 (1): 239-242.

B.A. Cardoso, L.R. Martins, C.I. Santos, L.M. Nadler, V.A. Boussiotis, A.A. Cardoso, J.T. Barata (2009).Interleukin-4 stimulates proliferation and growth of T-cell acute lymphoblastic leukemia cells by activating mTOR signaling. Leukemia 23 (1):206-208.

A. Silva, J.A. Yunes, B.A. Cardoso, L.R. Martins, P.Y. Jotta, M. Abecasis, A.E. Nowill, N.R. Leslie, A.A. Cardoso, J.T. Barata (2008) PTEN Posttranslational Inactivation and Hyperactivation of the PI3K/Akt Pathway Sustain Primary T Cell Leukemia Viability. Journal of Clinical Investigation 118 (11): 3762-3774.

J.T. Barata, A. Silva, J.G. Brandão, L.M. Nadler, A.A. Cardoso, V.A. Boussiotis (2004) Activation of PI3K is Indispensable for Interleukin 7-Mediated Viability, Proliferation, Glucose Use, and Growth of T Cell Acute Lymphoblastic Leukemia Cells. Journal of Experimental Medicine 200 (5): 659-669.

J.T. Barata, V.A. Boussiotis, J.A. Yunes, A.A. Ferrando, L.A. Moreau, J.P. Veiga, S.E. Sallan, A.T. Look, L.M. Nadler, A.A. Cardoso (2004). IL-7-dependent human leukemia T-cell line as a valuable tool for drug discovery in T-ALL. Blood 103 (5): 1891-1900.

J.T. Barata, A.A. Cardoso, L.M. Nadler, V.A. Boussiotis (2001). Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27kip1. Blood 98 (5): 1524-1531.

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