Our main interest is concerned with elucidating drug resistance mechanisms in cancer by large scale biological experiments using model systems followed by biomarker validation in clinical samples.
The computational and experimental biology group (CEB) aims at being forefront in clinical proteogenomics research. We have established experimental and computational quantitative technologies for MS-based profiling useful for clinical proteomics (e.g. label free quantitation, triple dimethyl labeling, SILAC and tandem tags).
We have considerable experience in large scale clinical proteomics. The aim of these projects is to discover novel protein or PTM signatures for diagnosis or prognosis of diseases. We have developed extensive computational methods for reporting on quality control parameters and reproducibility of clinical proteomics analysis based on LC-MS. The results are typically analyzed by a combination of machine learning and epidemiological computational methodologies.
The immune system’s ability to respond to environmental threats or stressors is directly involved in the development of human pathological conditions such as cancer. Indeed, immune checkpoint inhibitors (CPI) constitute a standard of care in genitourinary tumors, such as urothelial and renal cell carcinoma. However, clinical trials assessing the efficacy of CPIs in advanced prostate cancer (PCa) have been associated with low response rates, with benefits in only a minority of patients. In addition, there are areas that demands further consideration.
On average, 1 in 6 men develop clinically significant prostate cancer (csPCa) during lifetime and about 1 in 41 men will succumb because of the disease. In addition, the morbidities and significant reduction in quality-of-life associated with mistreatment of PCa raise critical concerns. Efforts are therefore in need to 1) predict risk assessment of a man's probability for developing prostate cancer during lifetime, 2) classify aggressive versus non-aggressive prostate cancer, 3) develop new treatments for aggressive disease, and 4) define the best treatment combinations of existing treatment strategies for optimal patient benefit.
We argue that since chronic persistent inflammation is associated to the early onset of PCa which harbors a predominance of immunosuppressive cells namely tumor-infiltrating lymphocytes (TILs) that has been associated with response to CPIs. The characterization of the immune system components pre and post systemic treatment across urological cancers using a multi-omics approach can bring light to the mechanisms involved in dismal response rates observed for PCa. Additionally, interest in new immunotherapeutic agents results from having observed that the expression of ligand 1 (PD-L1) of programmed cell death is increased in high-grade tumors.
These data suggest that increased expression of PD-L1 in the tumor environment may be associated with decreased response to immunotherapy, by promoting suppressor T cells. Thus, it is imperative to identify new, robust and reproducible molecular markers that can predict the response to immunotherapy, and simultaneously, identify other markers that can predict a better response to immunotherapeutic agents (anti-PD-L1/PD-1).
*) 27 main author (First, last or corresponding author) publications in international peer reviewed journals.
1. *) Is the Proteome of Bronchoalveolar Lavage Extracellular Vesicles a Marker of Advanced Lung Cancer?, Cancers, 2020-11-20 | journal-article DOI: 10.3390/cancers121134502. Comparative analysis of the bronchoalveolar microbiome in Portuguese patients with different chronic lung disorders. Seixas S, Kolbe AR, Gomes S, Sucena M, Sousa C, Vaz Rodrigues L, Teixeira G, Pinto P, Tavares de Abreu T, Bárbara C, Semedo J, Mota L, Carvalho AS, Matthiesen R, Marques PI, Pérez-Losada M. Sci Rep. 20213. Transcriptome Reprogramming of CD11bC Bone Marrow Cells by Pancreatic Cancer Extracellular Vesicles. Joana Maia1, Andreia Hanada Otake, Juliana Poças, Ana Sofia Carvalho, Hans Christian Beck, Ana Magalhaes, Rune Matthiesen,Maria Carolina Strano Moraes1 and Bruno Costa-Silva. Frontiers in Cell and Developmental Biology, accepted4. *) Diana Sousa, Rune Matthiesen*, Raquel T. Lima, M. Helena, Deep sequencing analysis reveals distinctive non-coding RNAs when comparing tumor multidrug resistant cells and extracellular vesicles with drug-sensitive counterparts, Cancers, 2020 Jan 14;12(1). pii: E200. doi: 10.3390/cancers120102005. Henriques AFA, Matos P, Carvalho AS, Azkargorta M, Elortza F, Matthiesen R, Jordan P. WNK1 phosphorylation sites in TBC1D1 and TBC1D4 modulate cell surface expression of GLUT1. Arch Biochem Biophys. 2019 Dec 6:108223. doi: 10.1016/j.abb.2019.108223. PMID: 318163126. *) Matthiesen R., MS-Based Biomarker Discovery in Bronchoalveolar Lavage Fluid for Lung Cancer. Proteomics Clin Appl. 20197. *) Carvalho AS, Baeta H, Silva BC, Moraes MCS, Bodo C, Beck HC, Rodriguez MS, Saraswat M, Pandey A, Matthiesen R. Extra-cellular vesicles carry proteome of cancer hallmarks. Front Biosci (Landmark Ed). 2020 Jan 1;25:398-436.8. Gomes S, Cavadas B, Ferreira JC, Marques PI, Monteiro C, Sucena M, Sousa C, Vaz Rodrigues L, Teixeira G, Pinto P, Tavares de Abreu T, Bárbara C, Semedo J, Mota L, Carvalho AS, Matthiesen R, Pereira L, Seixas S. Profiling of lung microbiota discloses differences in adenocarcinoma and squamous cell carcinoma. Sci Rep. 2019 Sep 6;9(1):12838. doi: 10.1038/s41598-019-49195-w.9. Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum. Santos JD, Canato S, Carvalho AS, Botelho HM, Aloria K, Amaral MD, Matthiesen R, Falcao AO, Farinha CM. Cells. 2019 Apr 14;8(4). pii: E353. doi: 10.3390/cells8040353.10. Lima RT, Sousa D, Gomes AS, Mendes N, Matthiesen R, Pedro M, Marques F, Pinto MM, Sousa E, Vasconcelos MH, The Antitumor Activity of a Lead Thioxanthone is Associated with Alterations in Cholesterol Localization.,Molecules. 2018 Dec 12;23(12)11. Canato S, Santos JD, Carvalho AS, Aloria K, Amaral MD, Matthiesen R, Falcao AO, Farinha CM. Proteomic interaction profiling reveals KIFC1 as a factor involved in early targeting of F508del-CFTR to degradation. Cell Mol Life Sci. 2018 (Q1)12. Interplay between SUMOylation and NEDDylation regulates RPL11 localization and function. El Motiam A, Vidal S, de la Cruz-Herrera CF, Da Silva-Álvarez S, Baz-Martínez M, Seoane R, Vidal A, Rodríguez MS, Xirodimas DP, Carvalho AS, Beck HC, Matthiesen R, Collado M, Rivas C. FASEB J., 2018 Jul, 30024791 (Q1)13. *) Ana Sofia Carvalho, C élia Marina Cuco, Carla Lavareda, Francisco Miguel, Mafalda Ventura, Sónia Almeida, Paula Pinto, Tiago Tavares de Abreu, Luís Vaz Rodrigues, Susana Seixas, Cristina Bárbara, Mikel Azkargorta, Felix Elortza, Júlio Semedo, John K Field, Leonor Mota, Rune Matthiesen, Bronchoalveolar Lavage Proteomics in Patients with Suspected Lung Cancer, Scientific Reports, 2017, Sci Rep. 2017 Feb 7;7:42190 (Q1)14. *) Jones-Dias D, Carvalho AS, Moura IB, Manageiro V, Igrejas G, Cani ça M, Matthiesen R. Quantitative proteome analysis of an antibiotic resistant Escherichia coli exposed to tetracy
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