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Cell Signalling, Epidemiology, Clinic and Cancer Therapy



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Group leader: Ana Bela Sarmento Ribeiro, José Manuel Nascimento Costa

Description:

This multidisciplinary group includes medical doctors with clinical, research and teaching activity and researchers from other areas such as biochemistry, genetics, molecular biology and pharmacy.

The main goals of this research group are the characterization of cellular and molecular mechanisms involved in cancer, drug sensitivity and resistance, in order to identify new prognostic and drug response markers and targets for therapies. We are particularly interested in the characterization of Cancer Stem Cells and immune system, in the identification of molecular markers related to cell signalling pathways (proliferative/survival and apoptotic), oxidative stress and mitochondria dysfunction, microRNAs and epigenetic/genetic modulation and the role of these processes in cancer susceptibility, diagnosis, prognosis and sensitivity/resistance to therapy. We also analysed the efficacy of new molecular targeted therapies, alone or in combination with other new drugs and/or conventional anticarcinogenic agents, identifying which of them will improve patient outcomes.

Finally, we also indented to correlate the results with patient’s clinical features, including transition to a more aggressive disease, survival and prognostic risk factors. On the other hand, by studying their interference with multidrug resistance mechanisms, we expect to be able to contribute to a better selection of molecular targeted therapeutic options.

Main achievements in the last 5 years:

1. Identification of susceptibility genes that can improve the understanding of leukemogenic mechanisms, offering the possibility to detect individuals at risk of developing hematological malignancies, as well as to identify potential biomarkers of disease progression and survival. Genetic variants in genes involved in oxidative stress, folate metabolism, DNA repair, and DNA methylation influence predisposition and prognosis of hematologic cancer as MDS and AML, as well as AML transformation rate in MDS patients. (Ana Cristina Gonçalves, et al., Ana Bela Sarmento-Ribeiro. Molecular Carcinogenesis. 2017) (10.1002/mc.22478)

2. Chronic antigen-stimulation has been recurrently involved in the earlier stages of monoclonal B-cell lymphocytosis (MBL) and other B-cell chronic lymphoproliferative disorders (B-CLPD/CLL). Molecular features of the BCR and cytogenetic profile of B-cell clones from the multiclonal versus monoclonal cases of MBL, CLL and other B-CLPD, reflects the multiclonality associated with early stages of B-CLPD and appears to reflect more closely an antigen-driven nature (with multiple and diverse antigenic determinants) of MBL and B-CLPD. (Henriques, A, Cortesao, E., et al., Paiva, A. Haematologica, 2014) 10.3324/haematol.2013.098913)

3. We show that aberrant DNA methylation is implicated in hematological neoplasia’s. Furthermore, we observed that SMD patients who have at least one methylated gene have a significant increase in peroxide expression levels when compared with patients with unmethylated genes. Moreover, patients with higher OS levels have an increase frequency of gene methylation and a lower survival; genetic polymorphisms in oxidative-stress related genes might be risk factors for the development of these neoplasias and may constitute novel genetic markers for myeloid neoplasia’s susceptibility (Gonçalves AC et al., 2013, Geraldes C, et al., Sarmento-Ribeiro AB. Clin Lymphoma Myeloma Leuk. 2016 Aug 10. pii: S2152-2650(16)30390-1. doi: 10.1016/j.clml.2016.08.016; AC Gonçalves et al., 2014; Ana Cristina Gonçalves, et al., Ana Bela Sarmento Ribeiro. Clin Exp Med. 2015 May 17: pp 1-11. DOI10.1007/s10238-015-0357-2).

4. We show that defects in cell death pathways and/or persistent oxidative stress and mitochondria dysfunction may be at the origin of certain hematological malignancies (e.g. leukemias and MDS), influence the prognosis, therapy response, and patients’ survival. On the other hand the serum erythropoietin levels is a predictive factor for response to therapy, and patients with myelodysplastic syndromes with higher values of erythropoietin have poorer response to administration of erythropoietin even at higher doses. We also show the involvement of Wnt/β-catenin pathway in maintenance of osteosarcoma stem-like cells, being a potential therapeutic target for this cancer (Gonçalves AC, et al., Nascimento Costa JM, Sarmento-Ribeiro AB. Free Radic Res. 2015; 49(9): 1081-94. 10.3109/10715762.2015.1035268; Gonçalves AC, Cortesão E, et al., Nascimento-Costa JM, Sarmento-Ribeiro AB. Clinical and Experimental Medicine, n. 17, p. 1-10, 2015; Emília Cortesão, et al., José M. Nascimento Costa, Ana B. Sarmento Ribeiro. Acta Med Port 2015 Nov-Dec; 28(6): 720-725. Martins-Neves SR, et al., Gomes CMF. Cancer Lett. 2018 Feb 1;414:1-15. doi: 10.1016/j.canlet.2017.11.004).

5. It was highlighted the therapeutic potential of compounds, such as vitamin C, selenium and cellular signalling inhibitors in several haematological neoplasias and solid cancers. We show in bladder cancer, that a cell-based immunotherapeutic approach are highly effective in the eradication of bladder CSCs. Moreover, we found that OS and apoptosis may be involved in chemoresistance in ALL and that influx/efflux transporters were involved on imatinib resistance, and administration of imatinib and Reversine 205 re-sensitize resistant cells. (Ana Cristina Gonçalves, et., al. Ana Bela Sarmento-Ribeiro. Biol Trace Elem Res 2013; Ana Cristina Gonçalves, et., Ana Bela Sarmento-Ribeiro. Toxicology in Vitro 2013; Margarida Ferreira-Teixeira, Belmiro Parada, Vitor Sousa, et al., Célia Gomes. BMC Medicine.2016, 14:163. DOI: 10.1186/s12916-016-0715-2; Alves R, et al., Sarmento-Ribeiro A.B.. Leukemia Research 2015, 39: 355–360. doi:http://dx.doi.org/10.1016/j.leukres.2014.12.008)

Selected Publications in the last 5 years:

1. Martins-Neves SR, Paiva-Oliveira DI, Fontes-Ribeiro C, Bovée JVMG, Cleton-Jansen AM, Gomes CMF. IWR-1, a tankyrase inhibitor, attenuates Wnt/β-catenin signaling in cancer stem-like cells and inhibits in vivo the growth of a subcutaneous human osteosarcoma xenograft. Cancer Lett. 2018 Feb 1;414:1-15. doi: 10.1016/j.canlet.2017.11.004. (IF= 6.375) Q1

2. Thierry Facon, Meletios A. Dimopoulos, Angela Dispenzieri, John V. Catalano, Andrew Belch, Michele Cavo, Antonello Pinto, Katja Weisel, Heinz Ludwig, Nizar J. Bahlis, Anne Banos, Mourad Tiab, Michel Delforge, Jamie D. Cavenagh, Catarina Geraldes, Je-Jung Lee, Christine Chen, Albert Oriol, Javier De La Rubia, Darrell White, Daniel Binder, Jin Lu, Kenneth C. Anderson, Philippe Moreau, Michel Attal, Aurore Perrot, Bertrand Arnulf, Lugui Qiu, Murielle Roussel,29 Eileen Boyle,1 Salomon Manier,1 Mohamad Mohty,30 Herve Avet-Loiseau,31 Xavier Leleu,32 Annette Ervin-Haynes,33 Guang Chen,33 Vanessa Houck,33 Lotfi Benboubker,34 and Cyrille Hulin. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018 Jan 18; 131(3): 301–310. doi:10.1182/blood-2017-07-795047. (IF= 13.164) Q1

3. Gonçalves AC, Alves R, Baldeiras I, Cortesão E, Carda JP, Branco CC, Oliveiros B, Loureiro L, Pereira A, Nascimento Costa JM, Sarmento-Ribeiro AB, Mota-Vieira L. Genetic variants involved in oxidative stress, base excision repair, DNA methylation, and folate metabolism pathways influence myeloid neoplasias susceptibility and prognosis. Molecular Carcinogenesis. 2017;56(1):130-148. doi: 10.1002/mc.22478. epub 2016 (IF=4,856) Q1

4. Bastos J, Rodrigues V, Paap E, Broeders M, Pina M, Cruz D, Carrito B, António Silva M. Breast cancer screening effectiveness in Portugal central Region. Eur J Cancer Prev. 2017 Sep;26,S204-S207. doi: 10.1097/CEJ.0000000000000376. (IF=3,031) Q1

5. Lapa, P., Oliveiros, B., Marques, M., (...), Costa, G., de Lima, J.P. Metabolic tumor burden quantified on [18F]FDG PET/CT improves TNM staging of lung cancer patients. European Journal of Nuclear Medicine and Molecular Imaging. 2017;44(13): 2169-2178. doi: 10.1007/s00259-017-3789-y (IF=7,277) Q1

6. Margarida Ferreira-Teixeira, Daniela Paiva‐Oliveira, Belmiro Parada, Vera Alves, Vitor Sousa, Obinna Chijioke, Christian Münz, Flávio Reis, Paulo Rodrigues-Santos, Célia Gomes. Natural Killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells. BMC Medicine.2016, 14:163. DOI: 10.1186/s12916-016-0715-2. (IF=8.097) Q1

7. Gonçalves AC, Cortesão E, B Oliveiros, Alves V, Espadana AI, Rito L, Magalhães E, Pereira S, Pereira A, Nascimento-Costa JM, Mota-Vieira L, Sarmento-Ribeiro AB. Oxidative stress levels are correlated with P15 and P16 gene promoter methylation in myelodysplastic syndrome patients. Clin Exp Med. 2016. 16(3):333-43. doi: 10.1007/s10238-015-0357-2. (IF: 2.919) Q2

8. Alves R, Fonseca AR, Gonçalves AC, Ferreira-Teixeira M, Lima J, Abrantes AM, Alves V, Rodrigues-Santos P, Jorge L, Matoso E, Carreira I, Botelho MF, Sarmento-Ribeiro A.B Drug transporters plays a key role in the complex process of Imatinib Resistance in vitro. Leukemia Research 2015, 39: 355–360. doi:http://dx.doi.org/10.1016/j.leukres.2014.12.008) (IF: 2.692) Q2

9. Gonçalves AC, Cortesão E, Oliveiros B, Alves V, Espadana AI, Rito L, Magalhães E, Lobão MJ, Pereira A, Nascimento Costa JM, Mota-Vieira L, Sarmento-Ribeiro AB. Oxidative stress and mitochondrial dysfunction play a role in myelodysplastic syndrome development, diagnosis, and prognosis: A pilot study. Free Radic Res. 2015; 49(9): 1081-94. Doi: 10.3109/10715762.2015.1035268 (IF= 2.949) Q1

10. Henriques A, Rodriguez-Caballero A, Criado I, Langerak AW, Nieto WG, Lecrevisse Q, Gonzalez M, Cortesao E, Paiva A, Almeida J, Orfao A. Molecular and cytogenetic characterization of expanded B-cell clones from multiclonal versus monoclonal B-cell chronic lymphoproliferative disorders. Haematologica 2014, v. 99, n. 5, p. 897-907,. doi:10.3324/haematol.2013.098913 (IF=5,814) Q1

People:

Integrated Members

Adélia Simão, PhD, MD

Amélia Pereira, PhD, MD

Ana Bela Sarmento Ribeiro, PhD, MD

Ana Cristina Gonçalves, PhD

Ana Paula Laranjeiro, PhD

António Bernardes, PhD, MD

Artur Paiva, PhD

Belmiro Parada, PhD, MD

Catarina Geraldes, PhD, MD

Célia Gomes, PhD

Emília Cortesão, PhD, MD

João Pimentel, PhD, MD

José Casanova, PhD, MD

José Manuel Nascimento Costa, PhD, MD

Letícia Ribeiro, PhD, MD

Luís Semedo, PhD, MD

Margarida Gonçalo, PhD, MD

Maria Manuel Donato, PhD

Marília Dourado, PhD, MD

Paula Laranjeira, PhD

Ricardo Vieira , PhD, MD

Vitor Rodrigues, PhD, MD

Vitor Sousa, PhD, MD

PhD Students:

André Ribeiro, MD

Fernanda Santos, MD

Inês Gois, MD

José Pedro Carda, MD

Luís Francisco, MD

Margarida Coucelo, MSc

Marta Pereira, MD

Raquel Alves, MSc

Teresa Louro, MSc

Colaborators:

Alberto Orfão, PhD, MD

Anabela Barros, MD

Cátia Domingues, MSc

Celeste Bento, PhD

Joana Jorge, MSc

Luísa Mota-Vieira, PhD

Paulo Donato, MD

Rosário Lebre, MD

Rui Garcia, MD

Teresa Fidalgo, PhD