Cancer Biology and Epigenetics Group
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
- Carmen Jerónimo, PhD
ORCID ID: 0000-0003-4186-5345
Scientific Coordinator of the Tumor Bank-Department of Pathology
Guest Full Professor at ICBAS-UP
Director of the Master Course in Oncology at ICBAS-UP
Guest Professor, School in Life Sciences, Università degli studi della Campania “Luigi Vanvitelli”, Naples, Italy
- Rui Henrique, MD, PhD
ORCID ID: 0000-0003-3171-4666
Consultant Pathologist, Department of Pathology
Guest Full Professor at ICBAS-UP
- Margareta P. Correia, PhD
ORCID ID: 0000-0003-4378-0820
- Bianca Troncarelli, PhD
ORCID ID: 0000-0002-6490-6309
- Carla Bartosch, MD, PhD
ORCID ID: 0000-0003-0646-7667
Pathologist at IPO Porto
- Nair Lopes, PhD
ORCID ID: 0000-0003-4732-7361
- Vânia Camilo, PhD
ORCID ID: 0000-0002-4661-8186
- Vera Miranda-Gonçalves, PhD
ORCID ID: 0000-0002-4231-5532
- Ana Catarina Macedo-Silva, MSc; Email: email@example.com
- Bárbara Costa Matos, MSc (Co-supervision-IBIMED/UA); firstname.lastname@example.org
- Catarina de Oliveira (Co-supervision-I3S); Email: email@example.com
- Daniela Barros-Silva, MSc; Email: firstname.lastname@example.org
- João Lobo, MD; Email: email@example.com
- Juliana Felgueiras, MSc (Co-supervision-IBIMED/UA); Email: firstname.lastname@example.org
- Nuno Coimbra, MD; Email: email@example.com
- Rita Canário, MD (Co-supervision-I3S); Email:firstname.lastname@example.org
- Sandra P. Nunes, MSc; Email: email@example.com
- Sara Monteiro-Reis, MSc; Email: firstname.lastname@example.org
- Sofia Salta, MSc; Email: email@example.com
- Tânia Lima, MSC; (Co-supervision-IBIMED/UA); Email: firstname.lastname@example.org
- Catarina Guimarães-Teixeira, MSc; Email: email@example.com
- Carina Carvalho-Maia, MSc; Email: firstname.lastname@example.org
- Cláudia Martins-Lima, MSc; Email: email@example.com
- Helena Estevão-Pereira; Email: firstname.lastname@example.org
- Leonardo Maia Moço; Email: email@example.com
- Mariana Brütt, MSc; Email: firstname.lastname@example.org
- Vera Constâncio, MSc; Email: email@example.com
- Ana Rita Cardoso; Email: firstname.lastname@example.org
- Bela Margarida Amaral Oliveira; Email: email@example.com
- Diana Rita Soares Fernandes; Email: firstname.lastname@example.org
- Filipa Moreira Silva; Email: email@example.com
- José Pedro Sequeira;Email: firstname.lastname@example.org
- Gonçalo Outeiro-Pinho; Email: email@example.com
Ana Isabel Varelas, MSc; Ana Luísa Cunha, MD; Paula Lopes, BSc; Ana Teresa Martins, MSc; Ângelo Rodrigues, MD; Catarina Meireles, MD; Davide Gigliano, MD; Fernanda Silva, BSc; Francisco Duarte Menezes, MD; Isa Carneiro, MSc; Joana Matos Loureiro, MD; João Pedro Costa, MSc; Jorge Torres-Ferreira, MSc; Madalena Souto Moura, MSc; Mariana Cantante, BSc; Mónica Domingos Farinha, MD; Paula Monteiro, MD; Paula Dias, BSc; Renata Vieira, BSc; Rita Guimarães, MSc; Sara Petronilho, MD; Sérgio Chacim, MSc; Sofia Paulino, MSc; Sónia Carvalho, MD; Verónica Ferreira, BSc.
The core aim of our group 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 responses, aiming at the improvement of immunotherapeutic strategies by combination with epi-drugs.
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. 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.
- Moreira-Silva F, Camilo V, Gaspar V, Mano JF, Henrique R, Jerónimo C. Repurposing Old Drugs into New Epigenetic Inhibitors: Promising Candidates for Prostate Cancer Treatment? Pharmaceutics 12; 410, 2020.
- Antunes J, Gaspar, VM, Ferreira, L, Monteiro, M, Henrique, R, Jeronimo, C and Mano, JF. In-air production of 3D co-culture tumor spheroid hydrogels for expedited drug screening. Acta Biomater. 94:392-409, 2019.
- 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. 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, Alzamora MA, Guimarães R, Cantante M, Lopes P, Braga I, Maurício J, Jerónimo C, Henrique R. p53 and MDM2 expression in primary and metastatic testicular germ cell tumors: Association with clinical outcome. Andrology 2020.
- Lobo J, Jerónimo C, Henrique R. Targeting the Immune system and Epigenetic Landscape of Urological Tumors. Int. J. Mol. Sci. 21(3), 829, 2020.
- Lobo J, Pinto C, Pinheiro M, Lobo F, Sousa N, Lopes P, Looijenga LHJ, Jerónimo C, Teixeira MR, Henrique R. Widening the spectrum of Lynch syndrome: first report of testicular seminoma attributable to MSH2 loss. Histopathology 76(3):486-489, 2020.
- Lobo, J, Rodrigues, A, Guimaraes, R, Cantante, M, Lopes, P, Mauricio, J, Oliveira, J, Jeronimo, C and Henrique, R. Detailed Characterization of Immune Cell Infiltrate and Expression of Immune Checkpoint Molecules PD-L1/CTLA-4 and MMR Proteins in Testicular Germ Cell Tumors Disclose Novel Disease Biomarkers. Cancers (Basel).11(10):1535, 2019.
- Lobo J, Nunes SP, Gillis AJM, Barros-Silva D, Miranda-Gonçalves V, van den Berg A, Cantante M, Guimarães R, Henrique R#, Jerónimo C#, Looijenga LHJ#. XIST-promoter demethylation as tissue biomarker for testicular germ cell tumors and spermatogenesis quality. Cancers 11(9), 2019.
- 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, Costa AL, Cantante M, Guimarães R, Lopes P, Antunes L, Braga I, Oliveira J, Pelizzola M, Henrique R, Jerónimo C.m6A RNA modification and its writer/reader VIRMA/YTHDF3 in testicular germ cell tumors: a role in seminoma phenotype maintenance. J Transl Med. 17(1):79, 2019.
- 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. 2018. doi: 10.2217/epi-2018-0034
Immunoprofiling characterisation of clinical samples by IHC and gene expression analysis and correlation with clinical outcomes in support of translational medicine strategies for ICOS and PD-L1-IC antibody therapeutics-KYmab, Budget: 99.723,20€ (2019-2021).
This project aims to support translational medicine work for the progression of programs from early discovery to clinical development via the strengthening of the understanding of target expression in clinically relevant human samples and correlation with clinical features of disease and outcome. Tissues used for this study are archived samples, currently part of the Department of Pathology, IPO-Porto tissue bank. Data generated, which will include protein and gene expression profiling of samples will allow the refinement of the clinical strategy of the KY1044 and KY1043 programmes. In addition, the evaluation of targets expressed by macrophages and/or dendritic cells across multi‑tumour tissues will be key for the assessment of their therapeutic relevance for cancer treatment.
PROJECTS WITH INTERNAL FUNDING
MethylBiom4Can– CI-IPOP-74-2016, Budget: 182.850,09€ (2016-2020)
Constâncio, V, Nunes, SP, Henrique, R and Jerónimo, C. DNA Methylation-Based Testing in Liquid Biopsies as Detection and Prognostic Biomarkers for the Four Major Cancer Types. Cells. 9(3), 2020.
Constâncio, V, Nunes, SP, Moreira-Barbosa, C, Freitas, R, Oliveira, J, Pousa, I, Oliveira, J, Soares, M, Dias, CG, Dias, T, Antunes, L, Henrique, R and Jeronimo, C. Early detection of the major male cancer types in blood-based liquid biopsies using a DNA methylation panel. Clinical epigenetics. 11(1):175, 2019.
Nunes SP, Diniz F, Moreira-Barbosa C, Constâncio V, Silva AV, Oliveira J, Soares M, Paulino S, Cunha AL, Rodrigues J, Antunes L, Henrique R, Jerónimo C. Subtyping Lung Cancer Using DNA Methylation in Liquid Biopsies. J Clin Med. 8(9). pii: E1500, 2019.
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.
Nunes SP, Moreira-Barbosa C, Salta S, Palma de Sousa S, Pousa I, Oliveira J, Soares M, Rego L, Dias T, Rodrigues J, Antunes L, Henrique R, Jerónimo C. Cell-Free DNA Methylation of Selected Genes Allows for Early Detection of the Major Cancers in Women. Cancers 10(10). pii: E357, 2018.
Salta S, Nunes SP et al. A DNA Methylation-Based Test for Breast Cancer Detection in Circulating Cell-Free DNA. J Clin Med. 7;7(11). pii: E420, 2018
Freitas M, Ferreira F, Carvalho S, Silva F, Lopes P, Antunes L, Salta S, Diniz F, Santos LL, Videira JF, Henrique R, Jerónimo C. A Novel DNA Methylation Panel Accurately Detects Colorectal Cancer Independently of Molecular Pathway J Transl Med 16(1):45, 2018.
MCTKidCan– CI-IPOP-92-2018, Budget: 55,000€ (2018-2020)
Miranda-Gonçalves V, Lameirinhas A, Henrique R, Baltazar F, Jerónimo C. The metabolic landscape of urological cancers: New therapeutic perspectives. Cancer Lett. 477:76-87, 2020.
Miranda-Gonçalves V, Lameirinhas A, Macedo-Silva C, Lobo J, C Dias P, Ferreira V, Henrique R, Jerónimo C. Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation. Cells 9(4):E1053. 2020.
Lameirinhas A, Miranda-Gonçalves V, Henrique R, Jerónimo C. The Complex Interplay between Metabolic Reprogramming and Epigenetic Alterations in Renal Cell Carcinoma. Genes 10(4). pii: E264, 2019.
- Outeiro-Pinho G, Barros-Silva D, Aznar E, Sousa AI, Vieira-Coimbra M, Oliveira J, Gonçalves CS, Costa BM, Junker K, Henrique R, Jerónimo C. MicroRNA-30a-5pme: a novel diagnostic and prognostic biomarker for clear cell renal cell carcinoma in tissue and urine samples. J Exp Clin Cancer Res. 39(1):98, 2020.
- Monteiro-Reis S, Lameirinhas A, Miranda-Gonçalves V, Felizardo D, Dias PC, Oliveira J, Graça I, Gonçalves CS, Costa BM, Henrique R, Jerónimo C. Sirtuins’ Deregulation in Bladder Cancer: SIRT7 Is Implicated in Tumor Progression through Epithelial to Mesenchymal Transition Promotion. Cancers (Basel). 12(5):E1066, 2020. (IF: 6.162)
- Barros-Silva D, Lobo J, Guimarães-Teixeira C, Carneiro I, Oliveira J, Martens-Uzunova ES, Henrique R, Jerónimo C. VIRMA-Dependent N6-Methyladenosine Modifications Regulate the Expression of Long Non-Coding RNAs CCAT1 and CCAT2 in Prostate Cancer. Cancers 12(4):E771, 2020. (IF: 6.162)
- Estevão-Pereira H, Lobo J, Salta S, Amorim M, Lopes P, Cantante M, Reis B, Antunes L, Castro F, Palma de Sousa S, Gonçalves CS, Costa BM, Henrique R, Jerónimo C. Overexpression of circulating MiR-30b-5p identifies advanced breast cancer. J Transl Med. 17(1):435, 2019. (IF: 4.098).
- Bidarra D, Constâncio V, Barros-Silva D, Ramalho-Carvalho J, Moreira-Barbosa C, Antunes L, Maurício J, Oliveira J, Henrique R, Jerónimo C. Circulating MicroRNAs as Biomarkers for Prostate Cancer Detection and Metastasis Development Prediction. Front Oncol. 9:900, 2019. (IF: 4.137)
- 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)
- 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)
- 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)
- 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)
(2012) Methods and biomarkers for detection of bladder cancer; US 20130210011/ EP 2630261 A1/ WO 2012052844 A1 (in collaboration Oslo University Hospital)
Dr. Bruno Costa-Silva, Fundação Champalimaud
Prof. Celso Reis, IPATIMUP, i3S
Prof. Joana Paredes, IPATIMUP, i3S
Prof. Fátima Baltazar & Dr. Bruno Costa, ICVS/3Bs, U. Minho
Profs. Fernando Jorge Monteiro & Susana Sousa; INEB, I3S
Prof. Goreti Sales, U. Coimbra
Prof. João F Mano, CICECO – U. Aveiro
Profs. Luisa Helguero & Margarida Fardilha, IBiMED, U. Aveiro
Prof. Maria José Oliveira, INEB, i3S
Dr. Meriem Lamghari, INEB, i3S
Prof. Paula Guedes & Prof. Márcia Carvalho, REQUIMTE-FF, U. Porto
Prof. Raquel Almeida, IPATIMUP, i3S
Dr. Renata Freitas, IBMC, i3S
Prof. Regina Silva, ESS, PP
Dr. Aamir Ahmed, King’s College London, UK
Prof. Antonio Lopez-Beltran, Cordoba University Medical School, Cordoba, Spain
Dr. Elena Martens-Uzunova, Erasmus Medical Center, Rotterdam, The Netherlands
Dr. Florence Le Calvez-Kelm, IARC, Lyon, France
Dr. Guro Lind, Radium Hospital, Oslo, Norway
Dr. Jesús M. Paramio, Molecular Oncology Unit, CIEMAT, & Instituto de Investigacion Hospital Universitario 12 de Octubre, Madrid, Spain
Prof. Leendert H. J. Looijenga, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Prof. Lucia Altucci, School in Life Sciences, Università degli studi della Campania “Luigi Vanvitelli”, Naples, Italy
Prof. Marianne G. Rots, Groningen, The Netherlands
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
Prof. Valérie Taly, Université Paris Descartes, Paris, France
Cancer Biology & Epigenetics Group@ ResearchGate
Cancer Biology & Epigenetics Group@ Facebook
European Epitranscriptomics Network (EPITRAN) https://epitran.eu/
Epigenetic Chemical Biology (EPICHEM) http://epichembio.eu/