João Barata Lab
Signaling in Cancer
Signaling in Cancer
Cancer is a genetic disease modulated by multiple non-genetic determinants. Our research seeks to shed light on the role that both cell-intrinsic aberrations (genetic and non-genetic) and microenvironmental factors play in tumor initiation and progression, metastasis, and response to treatment. Our goal is to characterize the mechanisms underlying these processes. Because cellular signaling is at the core of the ability of the cell to perceive and respond to alterations in the intracellular and extracellular environments (thereby being essential for cell homeostasis and cancer development) we place much of our focus on how deregulation of key signaling pathways promotes cancer at various stages. We use patient material and explore different strategies and in vitro and in vivo models to gain fundamental insights into cancer biology that can be leveraged for therapeutic purposes. We study acute lymphoblastic leukemia, the major childhood cancer, for many years, and have recently started to work on non-small cell lung cancer.
Cancer biology; signal transduction; targeted therapies; acute lymphoblastic leukemia; cellular and molecular biology
Our group aims to establish a dynamic research program focused on various aspects of cancer biology, with a primary emphasis on hematologic cancers, particularly T-cell acute lymphoblastic leukemia (T-ALL) and B-cell ALL (B-ALL). Because of our interest in how external cues contribute to cancer development, we have been studying the impact of interleukin 7 (which is produced by stromal cells) and its receptor (IL-7R), which is expressed by developing B- and T-cells, on the development of B-ALL and T-ALL. We have shown, for example, that IL-7 contributes to leukemia development in vivo (Silva et al, Cancer Res 2011) and that oncogenic gain-of-function mutations exist in T-ALL patients (Zenatti et al, Nat genet 2011). We also showed that IL7R mutations or IL7R overexpression can drive leukemia development in vivo (Almeida et al, Nat Commun 2021; Silva et al, Blood 2021; Oliveira et al, Leukemia 2022; Sumaria et al, Nat Immunology 2024). Ongoing work aims to explore outstanding questions related to how IL-7 and IL-7R promote leukemia development and resistant to therapy. Our omics and functional approaches have allowed us to identify new molecular players in IL-7R-mediated signaling that we are currently characterizing mechanistically and therapeutically. We have also identified potential oncogenes and tumor suppressors that may be involved in ALL development, whose role we are studying.
As part of an international consortium, we are also involved in the generation of T-ALL patient-derived xenografts of high-risk and relapse/refractory patients to generate a panel of samples that can be thoroughly investigated – we are interested in understanding and tackling what remains a major obstacle in this disease: why some patients either do not respond to therapy or relapse. These cases have a very poor outcome and are in special need of new therapies.
Also, we wish to study the role of IL7 and IL7R beyond leukemia. We are trying to dissect the role of IL7/IL7R in lung cancer development and metastasis and resistance to immunotherapy. This is being pursued by an international team that we coordinate, making use of clinical data and patient cohorts and our unique IL7R-related mouse models.
Our interest in leukemia extends beyond IL7-IL7R. Our findings show that signaling networks display circadian oscillations in ALL cells. We are exploring these observations for therapeutic purposes.
Finally, because we are not only excited by the drive to understand the basis of cancer but also by the goal of fully exploring the innovative translational potential of our research, we have also a product-oriented research vector (driven by Rita Fragoso), illustrated by our past proof-of-concept ERC-funded projects (IL7RsignaTHER and miRToTALL), which we continue to take forward.
2024-2027 ALLTogether team science: development of a preclinical testing platform to improve outcomes for drug resistant T-cell Acute Lymphoblastic Leukemia; Coordination: João Barata (local coordinator); Funding Agency: European Science Foundation
2024-2026: Dependence of IL-7R-mediated signaling on sphingosine kinase activity in acute lymphoblastic leukemia cells as an exploitable therapeutic vulnerability; Coordination: João Barata; Funding Agency: Worldwide Cancer Research.
2024-2025: Targeted chronotherapy in T-cell acute lymphoblastic leukemia; Coordination: João Barata; Funding Agency: iMM internal grant
2024-2025: Interleukin-7 receptor-mediated regulation of lipid metabolism as a potential target for therapeutic intervention in acute lymphoblastic leukemiaFunding Agency: Programa Gilead GÉNESE – Gilead Grants Program.
2022-2025: IL7R hijacking by lung cancer cells; Coordination: João Barata; Funding Agency: Fundação para a Ciência e Tecnologia
2021-2025: IL7R_LungCan – IL7R in lung cancer development, metastasis and resistance to immune checkpoint inhibitor therapy; Coordination: João Barata; Funding Agency: la Caixa Foundation
Sumaria N*, Fiala GJ*, Inácio D, Curado-Avelar M, Cachucho A, Pinheiro R, Wiesheu R, Kimura S, Courtois L, Blankenhaus B, Darrigues J, Suske T, Almeida ARM, Minguet S, Asnafi V, Lhermitte L, Mullighan CG, Coffelt SB, Moriggl R, Barata JT**, Pennington DJ**, Silva-Santos B** (2024) Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate interferon-γ producers that expand in IL-7R/STAT5B-driven neoplasms. Nat Immunol. 25(7):1207–1217. *Co-first authors; **Co-senior authors
Faria CC, Cascão R, Custódia C, Paisana E, Carvalho T, Pereira P, Roque R, Pimentel J, Miguéns J, Cortes-Ciriano I, Barata JT (2022) Patient-derived models of brain metastases recapitulate human disseminated disease. Cell Rep Med. 3(5):100623
Oliveira ML, Veloso A, Garcia EG, Iyer S, Pereira C, Barreto VM, Langenau DM*, Barata JT* (2022) Mutant IL7R collaborates with MYC to induce T-cell acute lymphoblastic leukemia. Leukemia. 36(6):1533–1540. *Co-senior authors
Almeida A, Neto JL, Cachucho A, Euzébio M, Meng X, Kim R, Fernandes MB, Raposo B, Oliveira ML, Ribeiro D, Fragoso R, Zenatti PP, Soares T, Matos MR, Ronchi Corrêa J, Duque M, Roberts KG, Gu Z, Qu C, Pyne S, Pyne NJ, Barreto VM, Bernard-Pierrot I, Clappier E, Mullighan CG, Grosso AR, Yunes JA*, Barata JT* (2021) Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia. Nat Commun. *Co-senior authors
Silva A*, Almeida A*, Cachucho A, Neto JL, Demeyer S, Matos M, Hogan T, Li Y, Meijerink JP, Cools J, Grosso AR, Seddon B**, Barata JT** (2021) Overexpression of wild type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma. Blood. 138(12):1040–1052. *Co-first authors; **Co-senior authors
Barata JT, Durum SK, Seddon B (2019) Flip the coin: IL-7 and IL-7R in health and disease. Nat Immunol. 20(12):1584–1593.
Akkapeddi P, Fragoso R, Hixon JA, Ramalho AS, Oliveira ML, Carvalho T, Gloger A, Matasci M, Corzana F, Durum SK, Neri D, Bernardes GJL*, Barata JT* (2019) A fully human anti-IL-7Rα antibody promotes antitumor activity against T-cell acute lymphoblastic leukemia. Leukemia. 33(9):2155–2168. *Co-senior authors
Sarmento LM, Póvoa V, Nascimento R, Real G, Antunes I, Martins LR, Moita C, Alves PM, Abecasis M, Moita LF, Parkhouse RME, Meijerink JP, Barata JT (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.
Pulido R, Baker SJ, Barata JT, […] Leslie NR (2014) A unified nomenclature and amino acid numbering for human PTEN. Sci Signal. 7(332):pe15.
Mendes RD*, Sarmento LM*, Canté-Barrett K, Zuurbier L, Buijs-Gladdines J, Póvoa V, Smits WK, Abecassis M, Yunes JA, Sonneveld E, Horstmann MA, Pieters R, Barata JT**, Meijerink JP** (2014) PTEN micro-deletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events. Blood. 124(4):567–578. *Co-first authors; **Co-senior authors
Silva A, Laranjeira ABA, Martins LR, Cardoso BA, Demengeot J, Yunes JA, Seddon B, Barata JT (2011) IL-7 contributes to the progression of human T-cell acute lymphoblastic leukemias. Cancer Res. 71(14):4780–4789.
Zenatti PP, Ribeiro D, Li W, Zuurbier L, Silva MC, Paganin M, Tritapoe J, Hixon JA, Silveira AB, Cardoso BA, Sarmento LM, Correia N, Toribio ML, Kobarg J, Horstmann M, Pieters R, Brandalise SR, Ferrando AA, Meijerink JP, Durum SK, Yunes JA**, Barata JT** (2011) Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet. 43(10):932–939. **Co-senior authors
Martins LR, Lúcio P, Silva MC, Gameiro P, Silva MG, Barata JT (2010) Targeting CK2 overexpression and hyperactivation as a novel therapeutic tool in chronic lymphocytic leukemia. Blood. 116(15):2724–2731.
Henriques CM, Rino J, Nibbs RJ, Graham GG, Barata JT (2010) IL-7 induces rapid clathrin-mediated internalization and JAK3-dependent degradation of IL-7Rα in T cells. Blood. 115(16):3269–3277.
Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M, Nowill AE, Leslie NR, Cardoso AA, Barata JT (2008) PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest. 118(11):3762–3774.
2023 Abstract Achievement Award (Highlighted ‘Best of ASH’ attributed to Marta Fernandes)
2021 Pfizer Award on Basic Research – Sociedade das Ciências Médicas de Lisboa.
2014 Pfizer Award on Clinical Research – Sociedade das Ciências Médicas de Lisboa
2013 Silver Medal for Distinct Services from the Portuguese Ministry of Health (attributed to J.T. Barata)
2012 Best Article in Immunology Award – Sociedade Portuguesa de Imunologia (SPI)
2011 Pfizer Award on Clinical Research – Sociedade das Ciências Médicas de Lisboa
2009 Pulido Valente Science Prize 2009 – Translational Molecular Oncology (Attributed to Ana Silva)
2008 Pfizer Award on Basic Research – Sociedade das Ciências Médicas de Lisboa.
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Past funders
Group leader
On the Verge of Discovery