The core aim of our group established in 2008 is to portray in depth the epigenetic/epitranscriptomic mechanisms involved in carcinogenesis. Biologically appropriate tumor models are studied to ascertain the patterns of epigenetic/epitranscriptomic alterations associated with malignant transformation, which might be used as clinical tools for early detection, diagnosis, prognostication and prediction of response to therapy. The investigation of epidrugs for cancer therapy is another major goal.
Moreover, owing to the relevance that Immuno-oncology has demonstrated in recent years, we are also investigating the epigenetic modulation of expression of biomolecules involved in immune checkpoint regulation, aiming at the improvement of immunotherapeutic strategies by combination with epi-drugs.
Cancer Biology and Epigenetics Group
ORCID ID: 0000-0003-4186-5345
Scientific Coordinator of the Tumor Bank-Department of Pathology
Invited Associate Prof.
with Aggregation at ICBAS-UP
Director of the Master Course in Oncology at ICBAS-UP
ORCID ID: 0000-0003-3171-4666
Director of the Department of Pathology
Director of the Tumor Bank of the Department Pathology
Invited Full Professor at ICBAS-UP
ORCID ID: 0000-0003-0646-7667
Pathologist at IPO Porto
Email: [email protected]
ORCID ID: 0000-0002-4661-8186
Email: [email protected]
- Vera Miranda-Gonçalves, PhD
ORCID ID: 0000-0002-4231-5532
Email: [email protected]
Carina Carvalho-Maia, MSc; Email: [email protected]
Catarina Guimarães-Teixeira; Cláudia Martins-Lima; Helena Estevão-Pereira, Gonçalo Outeiro-Pinho; Mariana Brütt; Rita Guimarães; Rita Silva-Oliveira; Vera Constâncio
Ana Luísa Cunha, MD; Paula Lopes, BSc; Ana S.
Pires-Luis, MD, PhD; Ana Teresa Martins, MSc; Ângelo Rodrigues, MD; Davide Gigliano, MD; Diana Montezuma, MD; Fernanda Silva, BSc; Filipa Quintela-Vieira, PhD; Francisco Duarte Menezes, MD; Inês Graça, PhD; Isa Carneiro, MSc; Joana Matos Loureiro, MD; Jorge Torres-Ferreira, MSc; Mª Conceição Martins, BSC; Mariana Cantante, BSc; Mónica Domingos Farinha, MD; Paula Monteiro, MD; Paula Dias, BSc; Renata Vieira, BSc; Sara Petronilho, MD; Sofia Paulino, MSc; Sónia Carvalho, MD; Verónica Ferreira, BSc.
Our research interests are focused on the characterization of the epigenome of tumor cells, as well as the identification of functional changes involved in the breakdown of cell epigenetic homeostasis.
In the context of Personalized Medicine, we are especially interested in the development of new cancer epigenetic biomarkers based in liquid biopsies as well as in the drug discovery for cancer based on the modulation of cancer-related epigenetic aberrations. Complementary to Epigenetics, our most recent area of interest is Epitranscriptomics, particularly N6-methyladenosine (m6A) that may impact in various cellular processes, through post-transcriptional regulation of gene expression.
Projects with External Funding
HyTherCaP- Hydralazine: Testing an off-label effect in Castration-Resistant Prostate Cancer FCT- POCI-01-0145-FEDER-29030, Budget: 196.448,85€ (2018-2020).
Prostate cancer (PCa) is one of the most commonly diagnosed malignancies worldwide and a leading cause of cancer-related deaths among men.
Cancer Biology and Epigenetics Group
In Portugal, it is the most incident cancer and the 3rd cause of death (1, 2). Although most of PCa are clinically indolent, a variable proportion of patients develop castration-resistant PCa (CRPC), an aggressive and lethal form of disease, associated with metastatic dissemination (3). Currently, most therapeutic strategies for CRPC are not curative and largely ineffective, only marginally increasing in survival (4).
Therefore, novel therapeutics strategies, ideally based on PCa biology, are urgently needed. Androgen receptor (AR) plays a central role in PCa development and progression. Androgen deprivation therapy is the standard initial care for metastatic PCa (5). Most resistance mechanisms to ADT are related with AR overexpression or mutations, amplification, alternative splice variants, and epigenetic alterations (6, 7). However, 20-30% of CRPC are characterized by a wide loss of AR expression (8, 9) which is not related to either mutations or deletions (10, 11).
Promoter hypermethylation is one of the main mechanisms for AR loss of expression (12, 13). Recently, we demonstrated that hydralazine, a non-nucleoside inhibitor of DNA methyltransferases (DNMTi), attenuates malignant phenotype of PCa cells (14).
Remarkably, CRPC cell line harboring AR promoter methylation, DU145, achieved the best drug response. Hydralazine restored AR expression and re-sensitized these cells to conventional androgen deprivation therapy, showing promise as innovative therapy for PCa. The major aims of this project are to confirm Hydralazine’s mechanism of action in CRPC and define which subgroup of CRPC patients will benefit from this therapy.
To achieve these goals, this project is based on the vast experience of a multidisciplinary team with knowhow in epigenetic editing, 2D and 3D in vitro cell culture, molecular biology, nanotechnology and pathology. The activities that will be carried out include a) AR in vitro methylation, in collaboration with an expert in this methodology; b) Assembly of 3D Prostate Cancer by CICECO members to test hydralazine effects in more complex cancer models; c) Test Hydralazine delivery in nanoliposomes, developed by NanoSTAR, to reduce drug concentration d) Identification of biomarkers predictive of response to hydralazine and subsequent validation in a cohort of PCa patients.
This activity as well as all pharmacological and phenotypic assays.
Marques-Magalhães Â, Graça I, Henrique R, Jerónimo C. Targeting DNA Methyltranferases in Urological Tumors.
Front Pharmacol 13;9:366, 2018.
EpiMarkGermCell-“DEVELOPMENT OF NOVEL PROGNOSTIC AND PREDICTIVE EPIGENETIC BIOMARKERS FOR MALIGNANT TESTICULAR GERM CELL TUMORS”- FCT- POCI-01-0145-FEDER-29043, Budget: 239.923,86€ (2018-2020).
This project aims to contribute to the improvement of care provided to patients with malignant testicular germ cell tumors (TGCT) and is a result of the recognition of IPO Porto (in partnership with Oporto Hospital Center) as a Reference Center for diagnosis and treatment of Testicular cancer.
Menu de navegação
In the North Region, according with the most recent data from RORENO (2011), the standardized incidence rate for testicular cancer is 4.3/100,000 (about 75 cases/year), being the most frequent cancer in young men (15- 44 years) . Similar values are observed worldwide, with the number of new cases expected to exceed 65,000 by 2030 .
Despite the excellent prognosis, about 15-20% of the patients with disseminated tumor develop recurrence, presenting poor prognosis. Some tumors are resistant to cisplatin therapy, and neither the underlying mechanisms are fully understood nor predictive biomarkers exist to identify tumors which are likely to endure cisplatin-resistance.
Finally, the sensitivity of serum markers in use is less than 60%, limiting patient monitoring and early identification of relapse. The PI and Co-PI research team has been dedicated for more than a decade to characterizing the epigenome of tumor cells by establishing the DNA methylation profile, post-translational histone modifications, and altered miRNA expression patterns, identifying functional alterations involved in the loss of epigenetic homeostasis.
This knowledge was translated into the development of epigenetic biomarkers aimed at the early detection, diagnosis, prognosis and prediction of response to therapy in urological tumors, favoring its use in clinical samples obtained by non-invasive or minimally invasive methods such as liquid biopsies, including plasma and urinary sediments.
Thus, panels of epigenetic markers for prostate (APC promoter methylation for prognostic stratification  and promoter methylation of genes encoding miR-34b/c, miR-129-2 and miR-193b for early prostate cancer detection in urine ), bladder (promoter methylation of GDF15, TMEFF2 and VIM for accurate detection in urine ) and kidney (expression levels of miR-141 and miR-200b for specific detection of major histological types and prognostication ) cancer.
Thus, we intend to develop a set of novel epigenetic biomarkers for TGCT, which can be analyzed in liquid biopsies, allowing for improved evaluation of prognosis and prediction of resistance to chemotherapy, aiding in monitoring during and after treatment. In addition to the experience accumulated in CEBG, we have the collaboration of Prof.
Leendert Looijenga (Erasmus University, Rotterdam), renowned researcher in this field, as a scientific consultant, permitting the use of state-of-the-art equipment for the discovery of new biomarkers (aberrant DNA methylation, chromatin remodeling enzymes and differential expression of microRNAs).
- Lobo J, Barros-Silva D, Henrique R, Jerónimo C.
The Emerging Role of Epitranscriptomics in Cancer: Focus on Urological Tumors. Genes 9(11). pii: E552, 2018.
- Lobo J, Henrique R, Jerónimo C.The Role of DNA/Histone Modifying Enzymes and Chromatin Remodeling Complexes in Testicular Germ Cell Tumors.
Cancers (Basel) 11(1). pii: E6., 2018.
- Lobo J, Costa AL, Vilela-Salgueiro B, Rodrigues Â, Guimarães R, Cantante M, Lopes P, Antunes L, Jerónimo C, Henrique R.
Testicular germ cell tumors: revisiting a series in light of the new WHO classification and AJCC staging systems, focusing on challenges for pathologists. Hum Pathol.
pii: S0046-8177 (18) 30283-1, 2018.
- Costa AL, Moreira-Barbosa C, Lobo J, Vilela-Salgueiro B, Cantante M, Guimarães R, Lopes P, Braga I, Oliveira J, Antunes L, Henrique R, Jerónimo C. DNA methylation profiling as a tool for testicular germ cell tumors subtyping.
Epigenomics. 2018. doi: 10.2217/epi-2018-0034
Projects with Internal Funding
MethylBiom4Can– CI-IPOP-74-2016, Budget: 152.850,09€ (2016-2019).
MCTKidCan– CI-IPOP-92-2018, Budget: 35,000€ (2018-2019).
- Graça I, et al.
Anti-neoplastic properties of hydralazine in prostate cancer.
Oncotarget. 5(15): 5950-64, 2014. (IF: 6.359)
- Bartosch C, et al. Pathologic Findings in Prophylactic and Nonprophylactic Hysterectomy Specimens of Patients With Lynch Syndrome.
Am J Surg Pathol 40(9):1177-91, 2016. (IF: 5.363)
- Ramalho-Carvalho J et al. Epigenetic disruption of miR-130a promotes prostate cancer by targeting SEC23B and DEPDC1.
Cancer Lett 385:150-159, 2017. (IF: 6.375)
- Padrao, NA, et al. MicroRNA promoter methylation: a new tool for accurate detection of urothelial carcinoma. Br J Cancer;116(5):634-9, 2017. (IF: 6.176)
- Torres-Ferreira J, et al.
MiR-193b promoter methylation accurately detects prostate cancer in urine sediments and miR-34b/c or miR-129-2 promoter methylation define subsets of clinically aggressive tumors.
Mol Cancer 16(1):26, 2017. (IF: 6.204)
- Ramalho-Carvalho J, et al. Downregulation of miR-130b~301b cluster is mediated by aberrant promoter methylation and impairs cellular senescence in prostate cancer. J Hematol Oncol 10(1):43, 2017. (IF: 7.333)
- Barros-Silva D, et al.
MicroRNA-27a-5p regulation by promoter methylation and MYC signaling in prostate carcinogenesis. Cell Death Dis 9(2):167, 2018. (IF: 5.638)
- Vilela-Salgueiro B, et al. Germ cell tumour subtypes display differential expression of microRNA371a-3p.
Philos Trans R Soc Lond B Biol Sci. 373, 2018.(IF: 5.666)
- Moreira-Barbosa C, et al. Comparing diagnostic and prognostic performance of two-gene promoter methylation panels in tissue biopsies and urines of prostate cancer patients. Clin Epigenetics. 10(1):132. 2018. (IF: 6.091)
- Salta S, Nunes SP et al.
Archives: Grupos de Investigação
A DNA Methylation-Based Test for Breast Cancer Detection in Circulating Cell-Free DNA. J Clin Med. 7;7(11). pii: E420, 2018 (IF: 5.583)
(2012) Methods and biomarkers for detection of bladder cancer; US 20130210011/ EP 2630261 A1/ WO 2012052844 A1 (in collaboration Oslo University Hospital)
Celso Reis, IPATIMUP, I3S
Prof. Fátima Baltazar & Dr. Bruno Costa, ICVS/3Bs, U. Minho
Profs. Fernando Jorge Monteiro & Susana Sousa; INEB, I3S
Prof. Goreti Sales, ISEP, PP
Prof. João F Mano, CICECO – U. Aveiro
Profs. Luisa Helguero & Margarida Fardilha, IBiMED, U. Aveiro
Prof. Maria Oliveira, INEB, I3S
Paula Guedes & Márcia Carvalho, REQUIMTE-FF, U. Porto
Dr. Renata Freitas, IBMC, I3S
Prof. Regina Silva, ESS, PP
Dr. Aamir Ahmed, King’s College London, UK
Antonio Lopez-Beltran, Cordoba University Medical School, Cordoba, Spain
Dr. Florence Le Calvez-Kelm, IARC, Lyon, France
Angelo rodrigues ipo poto
Guro Lind, Radium Hospital, Oslo, Norway
Prof. Leendert H. J. Looijenga, Erasmus MC, Rotterdam, the Netherlands, the Netherlands
Prof. Manel Esteller, IDIBELL Barcelona, Spain
Prof. Matthias Schwab, Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
Dr. Paola Arimondo, Institute Pasteur, Paris, France
Dr. Wilbert Zwart, NKI, Amsterdam, The Netherlands
Cancer Biology & Epigenetics [email protected] ResearchGate
Cancer Biology & Epigenetics [email protected] Facebook
European Epitranscriptomics Network (EPITRAN) https://epitran.eu/
Epigenetic Chemical Biology (EPICHEM) http://epichembio.eu/