Dr Patricia Madureira

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Dr Patricia Madureira

Senior Research Fellow at the Brain Tumour Research Centre of Excellence, University of Portsmouth, U.K.

Principal Investigator at Centre for Biomedical Research, University of Algarve, Portugal

 

Email:

patricia.madureira@port.ac.uk

Websites:

http://cbmr.ualg.pt/research/oncobiol/patriciam/

http://orcid.org/0000-0002-4856-3908

https://scholar.google.pt/citations?user=alULhlkAAAAJ&hl=pt-PT

https://www.researchgate.net/profile/Patricia_Madureira

Dr Patricia Madureira obtained a licenciatura (BSc) degree in Biochemistry from the Faculty of Sciences, University of Lisbon in 1998 and completed a PhD (supported by a fellowship from the Foundation for Science and Technology (FCT), Portugal) in Biomedical Sciences with Distinction from the Faculty of Medicine, University of Lisbon in 2005. She continued her scientific career as a postdoctoral fellow in Imperial College London, U.K. in Dr. Eric Lam´s laboratory, where she gained expertise in cancer cell signaling. Dr Madureira studied the role of FOXO and FOXM1 transcription factors in cancer cell biology and was awarded a postdoctoral fellowship from FCT for these studies. To further broaden her expertise in cancer research Dr Madureira became a senior postdoctoral fellow in Dalhousie University, Canada, working in Dr. David Waisman´s laboratory where she was awarded a Cancer Research Training Program postdoctoral fellowship to conduct these studies. Dr Madureira’s work focused on understanding the role of the plasminogen receptor, annexin A2-S100A10 heterotetramer (AIIt) in cancer cell invasion and fibrinolysis. She also developed independently a project in the novel area of reactive oxygen species (ROS) in cancer. Her work showed that annexin A2 plays a major role as an antioxidant protein in tumorigenesis, conferring resistance to chemotherapy and protection to DNA damage. Dr Madureira was awarded a prestigious WELCOME II principal investigator contract, co-funded by FCT and Marie Curie actions/ FP7 Program to establish her research laboratory in Portugal. Recently, Dr Madureira obtained a prestigious FCT Investigator award from the Foundation for Science and Technology, Portugal – a 5-year career development contract. She is a principal investigator in the Centre for Biomedical Research (CBMR), University of Algarve, Portugal and she been recently invited by Prof. Geoff Pilkington to join the Brain Tumour Research Centre of Excellence (BTRC) as an Invited Senior Research Fellow. Dr Madureira is an author in 23 papers, published in high impact international peer review journals, including Blood (IF:11.841), Nature Comms (IF:12), Cancer Research (IF:9.241), Oncotarget (IF:6.64), Cell Death & Disease (IF:6.04). Her h-index score is 17 and i-10 index is 17.

Research Interests

“My current research interests focus on understanding how cancer cells manipulate cellular systems in order to survive, proliferate and invade/ metastasize. Cancer cells typically have higher levels of reactive oxygen species (ROS) compared to their normal cell counterparts; this increase in ROS levels provides a proliferative advantage due to enhanced ROS-dependent signaling pathways that activate pro-survival and pro-proliferation signaling pathways. Nevertheless, excessive ROS can induce DNA, lipid and protein damage and ultimately lead to cell death. For this reason cancer cells up-regulate cellular antioxidant systems to avoid ROS overload. I have identified the protein annexin A2 as a novel redox regulatory protein that supports tumour growth and is involved in chemoresistance. Currently I am interested in investigating the role played by this protein in the regulation of ROS-dependent signaling pathways that have been shown to promote tumourigenesis.

During the development of a solid tumour, cancer cells have to survive in a hypoxic environment due to their very rapid and uncontrolled growth in conjunction with a poor/ defective blood supply that leads to lack of nutrients and oxygen. The hypoxia response leads to the activation of multiple cellular signaling pathways involved in the regulation of respiration, metabolism, cell survival, invasion and angiogenesis. Several studies have established that hypoxic cancer cells exhibit higher levels of ROS compared to non-hypoxic cancer cells. For this reason I am also interested in investigating if the antioxidant function of annexin A2 plays a role in cancer cell hypoxia. In the long run I would also like to identify and characterize other REDOX regulatory proteins whose expression are altered in human tumours and understand their role in cancer progression and chemoresistance.

As mentioned above, hypoxia typically induces cancer cell invasion. For this reason another main interest of my research is to investigate the contribution of the plasminogen receptor, annexin A2-S100A10 (AIIt) to cancer cell invasion particularly in the context of hypoxia. AIIt is responsible for about 40-80% of plasmin activation in different cancer cell lines. Plasmin is a protease that degrades components of the extracellular matrix and activates matrix metalloproteases, promoting in this way invasion/metastasis.

Recently I have become interested in focusing my research work in brain tumours for two main reasons. First, the high oxygen consumption of the brain advocates that oxidative stress might play an especially pertinent role in brain tumor formation and progression. However very little is known about the role of redox regulatory genes/ proteins (such as annexin A2) in brain tumorigenesis. Second, tumour hypoxia is particularly striking in glioblastoma (GBM), the most common and deadly type of primary brain tumour with an average life expectancy of less than 2 years following diagnosis. It is well established that hypoxia is a main trigger of cancer cell invasion and GBM migration and invasion into normal brain parenchyma is closely related to GBM patients’ poor prognosis and death. Several reports have shown elevated levels of annexin A2 in brain tumors. However, little is known about the molecular role of annexin A2 or its binding partner S100A10 in GBM. For this reason I would like to study if AIIt plays a role in plasmin regulation and subsequent enhanced invasive capability of GBM.

I am also interested in investigating if AIIt is involved in promoting brain metastasis, looking at solid tumours that frequently metastasize to the brain, such and lung and breast carcinomas. In the long run I would like to identify and characterize proteins that are involved in enhancing the invasive capability of brain cancer cells and in promoting brain metastasis.

Many chemotherapeutic agents used in the clinic rely at least partially in the production of ROS to kill cancer cells, the mechanisms by which this occurs can be linked to the release of ROS from the mitochondria (a major source of ROS in the cell). Unfortunately many cancer cells have up-regulated levels of antioxidant proteins that allow them to maintain a fine balance between low to intermediate levels of ROS that induce proliferative signalling and avoid elevated levels that induce cell death. This cancer cell REDOX adaptation can lead to chemoresistance. For this reason the development of new therapeutic approaches/strategies directed against redox regulatory proteins, such as annexin A2, in conjunction with currently used chemotherapeutic drugs (that trigger ROS-mediated cell death) may constitute more effective therapies against chemoresistant tumours.

It is currently known that cancer cell invasion and tumour microenvironment, particularly tumour angiogenesis, are closely related. Extracellular matrix and tumour microenvironment degradation by cancer cell activated proteases, such as plasmin and matrix metalloproteases, create spaces through which new blood vessels can penetrate the tumour. Taking into account that AIIt is an important plasminogen receptor, that regulates plasmin activity at the surface of many different types of cancer cells, it is reasonable to hypothesize that this protein complex might play a role not only in brain tumour invasion, but also in promoting tumour angiogenesis.

Many reports have also shown that both plasmin and its activator, tissue-type plasminogen activator (tPA) play an important role in regulating the permeability of the blood brain barrier (BBB). AIIt is able to bind to both plasminogen and tPA, bringing them together and promoting the activation of the inactive zymogen plasminogen into plasmin. However the role of AIIt in BBB permeability has not been investigated. It is fair to speculate that regulation of plasmin activity by AIIt might play a role in BBB permeability or even metastasis of cancer cells to the brain.”

Publications in peer review journals:

Miller VA, Madureira PA, Kamaludin AA, Komar J, Sharma V, Sahni G, Thelwell C, Longstaff C, Waisman DM. “Mechanism of plasmin generation by S100A10”. Thromb Haemost. 2017 Apr 6. doi: 10.1160/TH16-12-0936.

Hill R, Madureira PA, Ferreira B, Baptista I, Machado S, Colaço L, Dos Santos M, Liu N, Dopazo A, Ugurel S, Adrienn A, Kiss-Toth E, Isbilen M, Gure AO, Link W. “TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT”. Nat Commun. 2017 Mar 9; 8:14687. doi: 10.1038/ncomms14687

Madureira PA, Bharadwaj AG, Bydoun M, Garant K, O’Connell P, Lee P, Waisman DM. “Cell surface protease activation during RAS transformation: Critical role of the plasminogen receptor, S100A10.” Oncotarget. 2016 Jul 26;7(30):47720-47737. doi: 10.18632/oncotarget.10279. Impact factor (IF): 6.636. Classification: Q1. Highlighted news at Associação Portuguesa de Investigação em Cancro (ASPIC) website: http://www.aspic.pt/pt-pt/noticias/indu%C3%A7%C3%A3o-de-s100a10-por-ras-aumenta-capacidade-invasiva-de-c%C3%A9lulas-cancer%C3%ADgenas#.WHC4vvmLTIV

Castaldo SA, Freitas JR, Conchinha NV and Madureira PA. “The Tumorigenic Roles of the Cellular REDOX Regulatory Systems”. Oxid Med Cell Longev. 2016; 2016:8413032. doi: 10.1155/2016/8413032. IF: 4.492. Classification: Q1. Highlighted news at Associação Portuguesa de Investigação em Cancro (ASPIC) website: http://www.aspic.pt/pt-pt/noticias/os-sistemas-redox-na-progress%C3%A3o-do-cancro#.Vp85AxWLTIU

Hill R, Rabb M, Madureira PA, Clements D, Gujar SA, Waisman DM, Giacomantonio CA and Lee PWK. “Gemcitabine requires PUMA to drive tumour regression: implications for colon and pancreatic cancer therapy.”  Cell Death and Disease. 2013 Sep 5;4:e791. IF: 6.04. Classification: Q1.

Link W, Madureira PA and Hill R. “Identifying new targets for personalized cancer therapy”. eLS. 2013 May 15. DOI: 10.1002/9780470015902.a0024865. Review. IF: 2.119. Classification: Q2.

Madureira PA, Waisman DM. “Annexin A2: The importance of being redox sensitive.” Int J Mol Sci. 2013. Feb 7;14(2):3568-94. Review. IF: 3.257. Classification: Q1.

Madureira PA, O’Connell PA, Surette AP, Miller VA and Waisman DM. “The biochemistry and regulation of S100A10: a multifunctional plasminogen receptor involved in oncogenesis.” J Biomed Biotechnol. 2012 Oct; 2012:353687. Review. IF: 3.169. Classification: Q1.

Madureira PA, Hill R, Lee PWK and Waisman DM. “Genotoxic agents promote the nuclear accumulation of annexin A2: role of annexin A2 in mitigating DNA damage.” PLoS One. 2012 Nov; 7(11):e50591. IF: 3.537. Classification: Q1.

Madureira PA, Hill R, Giacomantonio C, Lee PWK, Waisman DM “Annexin A2 is a novel cellular redox regulatory protein involved in tumorigenesis.” Oncotarget. 2011 Dec; 2 (12):1075-93. IF: 6.636. Classification: Q1.

Hill R, Madureira PA, Waisman DM and Lee PWK. ” DNA-PKCS binding to p53 on the p21WAF1/CIP1 promoter blocks transcription resulting in cell death.” Oncotarget. 2011 Dec;2 (12):1094-108. IF: 6.636. Classification: Q1.

Madureira PA, Surette AP, Phipps KD, Taboski MAS, Miller VA and Waisman DM. “The role of the annexin A2 heterotetramer (AIIt) in vascular fibrinolysis.” Blood. 2011 Nov 3;118(18):4789-97. IF: 11.847. Classification: Q1.

Surette AP, Madureira PA, Phipps KD, Miller VA, Svenningsson P, Waisman DM. “Regulation of fibrinolysis by S100A10 in vivo.” Blood. 2011 Sep 15; 118(11):3172-81. IF: 11.847. Classification: Q1.

O’Connell PA, Madureira PA, Berman JN, Liwski RS, Waisman DM. “Regulation of S100A10 by the PML-RAR-α oncoprotein” Blood. 2011 Apr 14; 117(15):4095-105. IF: 11.847. Classification: Q1.

Madureira PA, Waisman DM . S100A10 (S100 calcium binding protein A10). Atlas Genet Cytogenet Oncol Haematol. October 2008.

Hill R, Leidal AM, Madureira PA, Gillis LD, Waisman DM, Chiu A, Lee PW. “Chromium-mediated apoptosis: Involvement of DNA-dependent protein kinase (DNA-PK) and differential induction of p53 target genes” DNA Repair (Amst). 2008 Sep 1;7(9):1484-99. IF: 4.274. Classification: Q1.

Hill R, Leidal AM, Madureira PA, Gillis LD, Cochrane HK, Waisman DM, Chiu A, Lee PW. “Hypersensitivity to chromium-induced DNA damage correlates with constitutive deregulation of upstream p53 kinases in p21-/- HCT116 colon cancer cells” DNA Repair (Amst). 2008 Feb 1;7(2):239-52. IF: 4.274. Classification: Q1.

Madureira PA, Varshochi R, Constantinidou D, Francis RE, Coombes RC, Yao KM, Lam EW. “The Forkhead box M1 protein regulates the transcription of the estrogen receptor alpha in breast cancer cells”. J Biol Chem 2006 Sep 1; 281 (35): 25167-76. IF: 5.117. Classification: Q1.

Madureira PA1, Sunters A1, Pomeranz KM, Aubert M, Brosens JJ, Cook SJ, Boudewijn MT, Burgering, Coombes RC, Lam EW, “Paclitaxel induced nuclear translocation of FOXO3a in breast cancer cells is mediated by JNK and PKB” Cancer Res. 2006 Jan 1; 66(1): 212-20.1These authors contributed equally to the work. IF: 8.65. Classification: Q1.

Labied S1, Kajihara T1, Madureira PA, Fusi L, Jones M, Higham JM, Varshochi R, Francis J, Zoumpoulidou G, Essafi A, Fernandez de Mattos S, Lam EW, Brosens JJ, “The Forkhead transcription factor FOXO1 regulates the menstrual switch”. Mol Endocrinol. 2006 Jan; 20(1): 35-44.1These authors contributed equally to the work. IF: 5.389. Classification: Q1.

Madureira PA, Matos P, Soeiro I, Dixon LK, Simas JP, Lam EW, “ MHV-68 gamma-herpesvirus latency protein M2 binds to Vav signalling proteins and inhibits BCR induced cell cycle arrest and apoptosis in WEHI-231 B cells”. J Biol Chem 2005 Nov 11; 280(45): 37310-8. IF: 5.117. Classification: Q1. Showcased in the online scientific magazine Ciência Hoje: http://www.cienciahoje.pt/index.php?oid=3690&op=all

Glassford J, Vigorito E, Soeiro I, Madureira PA, Zoumpoulidou G, Brosens JJ, Turner M, Lam EW, “Phosphatidylinositol 3-kinase is required for the transcriptional activation of cyclin D2 in BCR activated primary mouse B lymphocytes”. Eur J Immunol 2005 Sep; 35(9): 2748-61. IF: 5.103. Classification: Q1.

Varshochi R, Halim F, Sunters A, Alao JP, Madureira PA, Hart SM, Ali S, Vigushin DM, Coombes RC, Lam EW, “ICI182,780 induces p21Waf1 gene transcription through releasing HDAC1 and ERalpha from Sp1 sites to induce cell cycle arrest in MCF 7 breast cancer cell line”. J Biol Chem 2005 Feb 4; 280(5): 3185-96. IF: 5.117. Classification: Q1.

Book chapter:

International Manual of Oncology Practice. Principles of Medicaç Oncology. Madureira PA. Tumour Angiogenesis chapter. (2015) Springer publishers. http://www.springer.com/us/book/9783319216829

Project Grants:

Lead researcher

2015-2020: Exploratory project from Foundation for Science and Technology (FCT), Ref: IF/00614/2014/CP1234 – “Identification and characterization of redox regulatory proteins involved in cancer progression”.

2012-2015: Welcome II Programme contract, co-funded by Foundation for Science and Technology (FCT) and FP7/EU, Ref. DFRH/WIIA/26/2011 – “The role of annexin A2 protein in reactive oxygen species-dependent signalling”.

Collaborator

2011-2014: Natural Sciences and Engineering Research Council of Canada (NSERC) – “Role of annexin A2 as a scavenger of reactive oxygen species”.