Henrique Matos Fernandes de Oliveira Duarte
@i3s.up.pt
Junior Researcher at the Glycobiology in Cancer group
Institute for Research and Innovation in Health, University of Porto (i3S)
Junior Researcher and Project Leader at i3S, where he is dissecting the role played by cancer-associated glycosylation signatures in the emergence of molecular resistance to both conventional and targeted therapies in the advanced gastric cancer setting. His work has selected for presentation in multiple international scientific meetings related to Cancer Biology, and has been awarded as both the poster and oral communication (including the Porto Cancer Meeting). He has co-authored 15 publications in internationally recognized peer-reviewed journals (including high profile publications in Trends in Cancer, Oncogene, Cancer Cell, Molecular Aspects of Medicine, FEBS Letters, Plant Biotechnology journal), and 3 book chapters edited by prestigious scientific publishers (Nova Publishers, Wiley and Elsevier).
EDUCATION
HOD has an Integrated Master in Bioengineering, with a specialization in Molecular Biotechnology (2014, FEUP/ICBAS) awarded by the University of Porto, for which he was awarded with a Merit Scholarship for Exceptional Achievement as a student of the University of Porto by the Portuguese Ministry of Education (3rd best student of the 2009-2014 class).
HOD has an interntional PhD in Molecular and Cellular Biotechnology Applied to Health Sciences (ICBAS/FFUP, University of Porto, 2020), funded by FCT and the European Association for Cancer Research (EACR). Host Institution: Glycobiology in Cancer group of the Institute for Research and Innovation in Health, University of Porto (i3S) and the Center for Proteomics and Metabolomics of the Leiden University Medical Center (CPM/LUMC), Leiden, The Netherlands.
RESEARCH, TEACHING, or OTHER INTERESTS
Biotechnology, Cancer Research, Molecular Biology, Molecular Medicine
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Marta Baptista Freitas, Irene Gullo, Dina Leitão, Lúcia Águas, Carla Oliveira, António Polónia, Joana Gomes, Fátima Carneiro, Celso Albuquerque Reis, and Henrique Oliveira Duarte
MDPI AG
Gastric and gastroesophageal junction adenocarcinomas (GA/GEJA) are associated with a poor prognosis, primarily due to late disease diagnosis. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression and programmed death-ligand 1 (PD-L1) expression are important biomarkers for treatment selection in locally advanced unresectable and metastatic GA/GEJA, and there is increasing interest in their role in earlier stages of disease. In this study, we aimed to evaluate HER2 and PD-L1 expression in a curative-intent GA/GEJA cohort to describe their expression patterns and analyze the association between HER2 expression and clinicopathological features. HER2 expression was evaluated in surgical and endoscopic submucosal dissection tumor samples, and PD-L1 was evaluated in HER2-positive cases. The clinical cohort included 107 patients, with 8.4% testing positive for HER2 (seven of whom also exhibited a PD-L1 combined positive score of ≥1. HER2 status was not significantly associated with survival outcomes. A pathologist-guided, region-specific analysis revealed that PD-L1 expression rarely overlaps with HER2-positive tumor areas. While the therapeutic implications of these observations remain unknown, these findings suggest that combination strategies targeting HER2 and PD-L1 might be directed toward distinct tumor subclones. The herein disclosed region-specific biomarker expression patterns may have important therapeutic and prognostic impacts, warranting further evaluation.
Augusto Costa‐Barbosa, Diogo Ferreira, Maria Inês Pacheco, Margarida Casal, Henrique Oliveira Duarte, Catarina Gomes, Ana Margarida Barbosa, Egídio Torrado, Paula Sampaio, and Tony Collins
Wiley
AbstractChitinases are widely studied enzymes that have already found widespread application. Their continued development and valorisation will be driven by the identification of new and improved variants and/or novel applications bringing benefits to industry and society. We previously identified a novel application for chitinases wherein the Candida albicans cell wall surface chitinase 3 (Cht3) was shown to have potential in vaccine applications as a subunit antigen against fungal infections. In the present study, this enzyme was investigated further, developing production and purification protocols, enriching our understanding of its properties, and advancing its application potential. Cht3 was heterologously expressed in Pichia pastoris and a 4‐step purification protocol developed and optimised: this involves activated carbon treatment, hydrophobic interaction chromatography, ammonium sulphate precipitation, and gel filtration chromatography. The recombinant enzyme was shown to be mainly O‐glycosylated and to retain the epitopes of the native protein. Functional studies showed it to be highly specific, displaying activity on chitin, chitosan, and chito‐oligosaccharides larger than chitotriose only. Furthermore, it was shown to be a stable enzyme, exhibiting activity, and stability over broad pH and temperature ranges. This study represents an important step forward in our understanding of Cht3 and contributes to its development for application.
Shiva Izadi, Simon Gumpelmair, Pedro Coelho, Henrique O. Duarte, Joana Gomes, Judith Leitner, Vinny Kunnummel, Lukas Mach, Celso A. Reis, Peter Steinberger,et al.
Wiley
SummaryImmune checkpoint blocking therapy targeting the PD‐1/PD‐L1 inhibitory signalling pathway has produced encouraging results in the treatment of a variety of cancers. Durvalumab (Imfinzi®) targeting PD‐L1 is currently used for immunotherapy of several tumour malignancies. The Fc region of this IgG1 antibody has been engineered to reduce FcγR interactions with the aim of enhancing blockade of PD‐1/PD‐L1 interactions without the depletion of PD‐L1‐expressing immune cells. Here, we used Nicotiana benthamiana to produce four variants of Durvalumab (DL): wild‐type IgG1 and its ‘Fc‐effector‐silent’ variant (LALAPG) carrying further modifications to increase antibody half‐life (YTE); IgG4S228P and its variant (PVA) with Fc mutations to decrease binding to FcγRI. In addition, DL variants were produced with two distinct glycosylation profiles: afucosylated and decorated with α1,6‐core fucose. Plant‐derived DL variants were compared to the therapeutic antibody regarding their ability to (i) bind to PD‐L1, (ii) block PD‐1/PD‐L1 inhibitory signalling and (iii) engage with the neonatal Fc receptor (FcRn) and various Fcγ receptors. It was found that plant‐derived DL variants bind to recombinant PD‐L1 and to PD‐L1 expressed in gastrointestinal cancer cells and are able to effectively block its interaction with PD‐1 on T cells, thereby enhancing their activation. Furthermore, we show a positive impact of Fc amino acid mutations and core fucosylation on DL's therapeutic potential. Compared to Imfinzi®, DL‐IgG1 (LALAPG) and DL‐IgG4 (PVA)S228P show lower affinity to CD32B inhibitory receptor which can be therapeutically favourable. Importantly, DL‐IgG1 (LALAPG) also shows enhanced binding to FcRn, a key determinant of serum half‐life of IgGs.
Henrique O. Duarte, Joana Gomes, and Celso A. Reis
Wiley
Henrique O. Duarte, Celso A. Reis, and Joana Gomes
Elsevier BV
Francisca Diniz, Pedro Coelho, Henrique O. Duarte, Bruno Sarmento, Celso A. Reis, and Joana Gomes
MDPI AG
Innovative strategies have been proposed to increase drug delivery to the tumor site and avoid cytotoxicity, improving the therapeutic efficacy of well-established anti-cancer drugs. Alterations in normal glycosylation processes are frequently observed in cancer cells and the resulting cell surface aberrant glycans can be used as direct molecular targets for drug delivery. In the present review, we address the development of strategies, such as monoclonal antibodies, antibody–drug conjugates and nanoparticles that specific and selectively target cancer-associated glycans in tumor cells. The use of nanoparticles for drug delivery encompasses novel applications in cancer therapy, including vaccines encapsulated in synthetic nanoparticles and specific nanoparticles that target glycoproteins or glycan-binding proteins. Here, we highlight their potential to enhance targeting approaches and to optimize the delivery of clinically approved drugs to the tumor microenvironment, paving the way for improved personalized treatment approaches with major potential importance for the pharmaceutical and clinical sectors.
Rafaela Abrantes, Henrique O. Duarte, Catarina Gomes, Sébastien Wälchli, and Celso A. Reis
Wiley
Chimeric antigen receptor (CAR)‐T‐cell therapy is a promising anticancer treatment that exploits the host's immune system to fight cancer. CAR‐T cell therapy relies on immune cells being modified to express an artificial receptor targeting cancer‐specific markers, and infused into the patients where they will recognize and eliminate the tumour. Although CAR‐T cell therapy has produced encouraging outcomes in patients with haematologic malignancies, solid tumours remain challenging to treat, mainly due to the lack of cancer‐specific molecular targets and the hostile, often immunosuppressive, tumour microenvironment. CAR‐T cell therapy also depends on the quality of the injected product, which is closely connected to CAR design. Here, we explain the technology of CAR‐Ts, focusing on the composition of CARs, their application, and limitations in cancer therapy, as well as on the current strategies to overcome the challenges encountered. We also address potential future targets to overcome the flaws of CAR‐T cell technology in the treatment of cancer, emphasizing glycan antigens, the aberrant forms of which attain high tumour‐specific expression, as promising targets for CAR‐T cell therapy.
Ana Magalhães, Henrique O. Duarte, and Celso A. Reis
Elsevier
Joana G. Rodrigues, Henrique O. Duarte, Catarina Gomes, Meritxell Balmaña, Álvaro M. Martins, Paul J. Hensbergen, Arnoud H. de Ru, Jorge Lima, André Albergaria, Peter A. van Veelen,et al.
Springer Science and Business Media LLC
Ana Magalhães, Henrique O. Duarte, and Celso A. Reis
Elsevier BV
Henrique O. Duarte, Joana G. Rodrigues, Catarina Gomes, Paul J. Hensbergen, Agnes L. Hipgrave Ederveen, Arnoud H. de Ru, Stefan Mereiter, António Polónia, Elisabete Fernandes, José A. Ferreira,et al.
Springer Science and Business Media LLC
AbstractThe clinical performance of the therapeutic monoclonal antibody trastuzumab in the treatment of ErbB2-positive unresectable gastric cancer (GC) is severely hampered by the emergence of molecular resistance. Trastuzumab’s target epitope is localized within the extracellular domain of the oncogenic cell surface receptor tyrosine kinase (RTK) ErbB2, which is known to undergo extensive N-linked glycosylation. However, the site-specific glycan repertoire of ErbB2, as well as the detailed molecular mechanisms through which specific aberrant glycan signatures functionally impact the malignant features of ErbB2-addicted GC cells, including the acquisition of trastuzumab resistance, remain elusive. Here, we demonstrate that ErbB2 is modified with both α2,6- and α2,3-sialylated glycan structures in GC clinical specimens. In-depth mass spectrometry-based glycomic and glycoproteomic analysis of ErbB2’s ectodomain disclosed a site-specific glycosylation profile in GC cells, in which the ST6Gal1 sialyltransferase specifically targets ErbB2 N-glycosylation sites occurring within the receptor’s trastuzumab-binding domain. Abrogation of ST6Gal1 expression reshaped the cellular and ErbB2-specific glycomes, expanded the cellular half-life of the ErbB2 receptor, and sensitized ErbB2-dependent GC cells to trastuzumab-induced cytotoxicity through the stabilization of ErbB dimers at the cell membrane, and the decreased activation of both ErbB2 and EGFR RTKs. Overall, our data demonstrates that ST6Gal1-mediated aberrant α2,6-sialylation actively tunes the resistance of ErbB2-driven GC cells to trastuzumab.
Joana G. Rodrigues, Henrique O. Duarte, Celso A. Reis, and Joana Gomes
Portland Press Ltd.
Aberrant cell surface glycosylation signatures are currently known to actively drive the neoplastic transformation of healthy cells. By disrupting the homeostatic functions of their protein carriers, cancer-associated glycans mechanistically underpin several molecular hallmarks of human malignancy. Furthermore, such aberrant glycan structures play key roles in the acquisition of molecular resistance to targeted therapeutic agents, which compromises their clinical efficacy, by modulating tumour cell aggressiveness and supporting the establishment of an immunosuppressive microenvironment. Recent advances in the study of the tumour cell glycoproteome have unravelled previously elusive molecular mechanisms of therapeutic resistance, guided the rational design of novel personalized therapeutic strategies, and may further improve the clinical performance of currently approved anti-cancer targeted agents. In this review, we highlight the impact of glycosylation in cancer targeted therapy, with particular focus on receptor tyrosine kinase-targeted therapy, immune checkpoints blockade therapy, and current developments on therapeutic strategies directed to glycan-binding proteins and other innovative glycan therapeutic strategies.
Beatriz Leão, Xiaogang Wen, Henrique O. Duarte, Irene Gullo, Gilza Gonçalves, Patrícia Pontes, Claudia Castelli, Francisca Diniz, Stefan Mereiter, Joana Gomes,et al.
MDPI AG
Microsatellite instability (MSI) is a molecular phenotype due to a deficient DNA mismatch repair (dMMR). In colorectal cancer (CRC), dMMR/MSI is associated with several clinical and histopathological features, influences prognosis, and is a predictive factor of response to therapy. In daily practice, dMMR/MSI profiles are identified by immunohistochemistry and/or multiplex PCR. The Thomsen–Friedenreich (TF) antigen was previously found to be a potential single marker to identify MSI-high gastric cancers. Therefore, in this study, we aimed to disclose a possible association between TF expression and MSI status in CRC. Furthermore, we evaluated the relationship between TF expression and other clinicopathological features, including patient survival. We evaluated the expression of the TF antigen in a cohort of 25 MSI-high and 71 microsatellite stable (MSS) CRCs. No association was observed between the expression of the TF antigen and MSI-high status in CRC. The survival analysis revealed that patients with MSI-high CRC showed improved survival when the TF antigen was expressed. This finding holds promise as it indicates the potential use of the TF antigen as a biomarker of better prognosis in MSI-high CRCs that should be validated in an independent and larger CRC cohort.
Henrique O. Duarte, Joana Gomes, José C. Machado, and Celso A. Reis
Wiley
AbstractDespite major breakthroughs in the field of personalized medicine, gastric cancer (GC) remains a clinically challenging disease, characterized by scarce effective treatment options and the lack of reliable molecular tools for the prediction of patient outcome and response to therapy. The pronounced molecular heterogeneity that dictates the phenotypical aggressiveness of gastric neoplasms severely limits the antitumor efficacy of targeted agents brought to clinical trials, and constitutes a favorable setting for the emergence of refractory tumors exhibiting multidrug resistance. We will review the most recent advances in our understanding of GC biology, which are underlying the development and clinical testing of novel targeted therapeutic agents. We will also emphasize how their efficacy and acquired resistance relate to the aberrant molecular signatures that drive gastric malignancy.
Daniela Barros-Silva, Pedro Costa-Pinheiro, Henrique Duarte, Elsa Joana Sousa, Adriane Feijó Evangelista, Inês Graça, Isa Carneiro, Ana Teresa Martins, Jorge Oliveira, André L. Carvalho,et al.
Springer Science and Business Media LLC
AbstractUpregulation of MYC and miRNAs deregulation are common in prostate cancer (PCa). Overactive MYC may cause miRNAs’ expression deregulation through transcriptional and post-transcriptional mechanisms and epigenetic alterations are also involved in miRNAs dysregulation. Herein, we aimed to elucidate the role of regulatory network between MYC and miRNAs in prostate carcinogenesis. MYC expression was found upregulated in PCa cases and matched precursor lesions. MicroRNA’s microarray analysis of PCa samples with opposed MYC levels identified miRNAs significantly overexpressed in high-MYC PCa. However, validation of miR-27a-5p in primary prostate tissues disclosed downregulation in PCa, instead, correlating with aberrant promoter methylation. In a series of castration-resistant PCa (CRPC) cases, miR-27a-5p was upregulated, along with promoter hypomethylation. MYC and miR-27a-5p expression levels in LNCaP and PC3 cells mirrored those observed in hormone-naíve PCa and CRPC, respectively. ChIP analysis showed that miR-27a-5p expression is only regulated by c-Myc in the absence of aberrant promoter methylation. MiR-27a-5p knockdown in PC3 cells promoted cell growth, whereas miRNA forced expression in LNCaP and stable MYC-knockdown PC3 cells attenuated the malignant phenotype, suggesting a tumor suppressive role for miR-27a-5p. Furthermore, miR-27a-5p upregulation decreased EGFR/Akt1/mTOR signaling. We concluded that miR-27a-5p is positively regulated by MYC, and its silencing due to aberrant promoter methylation occurs early in prostate carcinogenesis, concomitantly with loss of MYC regulatory activity. Our results further suggest that along PCa progression, miR-27a-5p promoter becomes hypomethylated, allowing for MYC to resume its regulatory activity. However, the altered cellular context averts miR-27a-5p from successfully accomplishing its tumor suppressive function at this stage of disease.
Henrique Duarte, Meritxell Balmaña, Stefan Mereiter, Hugo Osório, Joana Gomes, and Celso Reis
MDPI AG
Aberrant expression and hyperactivation of the human epidermal growth factor receptor 2 (ErbB2) constitute crucial molecular events underpinning gastric neoplastic transformation. Despite ErbB2 extracellular domain being a well-known target for glycosylation, its glycosylation profile and the molecular mechanisms through which it actively tunes tumorigenesis in gastric cancer (GC) cells remain elusive. We aimed at disclosing relevant ErbB2 glycan signatures and their functional impact on receptor’s biology in GC cells. The transcriptomic profile of cancer-relevant glycosylation enzymes, and the expression and activation of the ErbB receptors were characterized in four GC cell lines. Cellular- and receptor-specific glycan profiling of ErbB2-overexpressing NCI-N87 cells unveiled a heterogeneous glycosylation pattern harboring the tumor-associated sialyl Lewis a (SLea) antigen. The expression of SLea and key enzymes integrating its biosynthetic pathway were strongly upregulated in this GC cell line. An association between the expression of ERBB2 and FUT3, a central gene in SLea biosynthesis, was disclosed in GC patients, further highlighting the crosstalk between ErbB2 and SLea expression. Moreover, cellular deglycosylation and CA 19.9 antibody-mediated blocking of SLea drastically altered ErbB2 expression and activation in NCI-N87 cells. Altogether, NCI-N87 cell line constitutes an appealing in vitro model to address glycan-mediated regulation of ErbB2 in GC.
Ana Magalhães, Henrique O. Duarte, and Celso A. Reis
Elsevier BV
Henrique Duarte, Daniela Freitas, Catarina Gomes, Joana Gomes, Ana Magalhães, and Celso Reis
MDPI AG
Mucin-type O-glycosylation plays a crucial role in several physiological and pathological processes of the gastric tissue. Modifications in enzymes responsible for key glycosylation steps and the consequent abnormal biosynthesis and expression of their glycan products constitute well-established molecular hallmarks of disease state. This review addresses the major role played by mucins and associated O-glycan structures in Helicobacter pylori adhesion to the gastric mucosa and the subsequent establishment of a chronic infection, with concomitant drastic alterations of the gastric epithelium glycophenotype. Furthermore, alterations of mucin expression pattern and glycan signatures occurring in preneoplastic lesions and in gastric carcinoma are also described, as well as their impact throughout the gastric carcinogenesis cascade and in cancer progression. Altogether, mucin-type O-glycosylation alterations may represent promising biomarkers with potential screening and prognostic applications, as well as predictors of cancer patients’ response to therapy.