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).

Current:

• 2022-2025: Optimizing mass spectrometry based detection of biomarkers for immunotherapy response across urologic cancers, PTDC/BTM-TEC/1746/2021, 250000,- Euro (Principal Investigator)
• 2021-2025: COST action “"A sound proteome for a sound body: targeting proteolysis for proteome remodeling (ProteoCure)" (CA20113)”
• 2019-2025: CEEC position (FCT), CEECIND/03906/2017, investigator position.
• 2018-2021: Portugal 2020, 02/SAICT/2017, 30088, Immune- and microenvironment- proteogenomics profiling for classifying lung cancer patients, budget 239769,36 Euro (Principal Investigator)
• 2018-2021: Portugal 2020, 02/SAICT/2017, 30087, Impact of B-cell deregulated pathways on tumor immune evasion - relevance for Diffuse Large B-Cell Lymphoma therapy response-LED, budget 239769,36 Euro (Co-Principal Investigator)
• 2017-2021: MEDIRAD: Implications of Medical Low Dose Radiation Exposure (HORIZON2020 NGRP-2016-2017-1) (Participant)​
• 2018-2022: ITN UBICODE, (Research member/associated partner) 3407194,- Euro (http://cordis.europa.eu/project/rcn/211533_en.html)

Upcoming:

• 2021-2026: Janssen 120000,- Euro (Responsible for scientific part of project)
• 2021-2022: Terry Fox 1500,- Euro (participant)
• 2021-2023: APU 10000,- Euro (participant)
• 2021-2023: CHULC 5000,- Euro (participant)

Previous:

• 2018-2020 Diffuse Large B-cell lymphoma blood based proteome signatures, iNOVA4Health, 48,125 Euro, Principal Investigator
• 2018-2021: Recovering neurofunction and promoting neuroprotection in diabetic retinopathy, (research member), FCT ACC 02/SAICT/2017, 239769,36 Euro
• 2018-2021 Lysosome dysfunction in age-related diseases, (research member), FCT ACC 02/SAICT/2017, 250000,- Euro
• 2018-2021 Molecular mechanisms in melanin-containing compartments, 29765, (research member), FCT ACC 02/SAICT/2017, 239769,36 Euro
• 2018-2021 Remote ischemic post-conditioning in acute phase of ischemic stroke – disclosing novel circulating biomarkers and clinical trial for improving outcome, (research member), FCT ACC 02/SAICT/2017, 239769,36,- Euro
• 2018-2021 Targeting RAC1-signaling to enhance iodide-related cancer therapy, (research member), FCT ACC 02/SAICT/2017, 239769,36 Euro
• 2016-2019: PTDC/BBB-BEP/2463/2014 ProbeCOPD. Protease activity-based probes for Chronic Obstructive Pulmonary Disease diagnostics ~200,000.00 Euro.
• 2014-2018: Remote ischemic per-conditioning in acute stroke – clinical trial for improving outcome and disclosing novel circulating biomarkers, iNOVA for health, (Research member) - 100,000.00 Euro.
  FCT investigator programme 2012 (Principal Investigator) – five year group leader salary.
• 2014-2019: National representative for the COST action PROTEOSTASIS, Principal Investigator
• 2014-2015: EXPL/DTP-PIC/0616/2013 “Global MS-based profiling of bronchial aspirate: targeting lung cancer specific modifications” (Principal Investigator) - 49,800.00 Euro.
• 2013-2015: PTDC-BEX-GMG-0242-2012 “Evaluating the role of proteolysis in the male reproductive system through the study of KLK (19q13.4) and WFDC (20q13) gene clusters.” (Research member)- ~200,000.00 Euro.
• 2010-2013: PTDC/QUI-BIQ/099457/2008 “Dissection of the molecular role of O-GlcNAc in the multinucleation phenotype of the neoplasic cells in Hodgkin´s lymphoma.” (Principal Investigator) ~200,000.00 Euro.
• 2010-2013: PTDC/EIA-EIA/099458/2008 “Computational disease prediction system based on molecular markers” (Principal Investigator) ~50,000.00 Euro.
• 2010-2013: PTDC/SAU-FCF/100930/2008 “Molecular and nanotechnology-based approaches to improve the antitumor activity of small molecules” (Research member) ~200,000.00 Euro.
• 2010-2013: PTDC/SAU-GMG/101229/2008 “Search for genomic structural variants in azoospermia: a study in Portuguese population ”
  Contract with Novo Nordisk (2010) - 10,000.00 Euro.
  Ramon Cajal (Principal Investigator) – five year group leader salary.
  Carlsberg foundation (Principal Investigator) – two year post doc salary.

1. Shotgun mass spectrometry-based lipid profiling identifies and distinguishes between chronic inflammatory disease
2. Is the Proteome of Bronchoalveolar Lavage Extracellular Vesicles a Marker of Advanced Lung Cancer?
3. Extra-cellular vesicles carry proteome of cancer hallmarks

*) 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/cancers12113450

2. 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. 2021

3. 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, accepted

4. *) 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/cancers12010200

5. 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: 31816312

6. *) Matthiesen R., MS-Based Biomarker Discovery in Bronchoalveolar Lavage Fluid for Lung Cancer. Proteomics Clin Appl. 2019

7. *) 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

• 2021 - Liga Portuguesa Contra o Cancro/MD Rui Miguel Bernadino
• 2020 - Portuguese Association Urology Grant/MD Rui Miguel Bernadino
• 2019-2025 -  CEEC position (FCT) investigator position/Rune Matthiesen.
• SPP/ Pfizer Vaccines 2016 – 10.000,- Euro/MD Amélia Feliciano
• FCT Investigator 2012 – Five year group leader salary/Rune Matthiesen
• Ciencia 2008 – Five year group leader salary/Rune Matthiesen
• Ramon y Cajal (RYC-2006-001446) – Five year group leader salary/Rune Matthiesen
• Carlsberg foundation 2004 – two year post doc salary/Rune Matthiesen

• Miguel Seabra, CEDOC: Lysosome dysfunction in age-related diseases
• Paula Macedo, CEDOC: Exosomes in diabetes
• Duarte Barral, CEDOC
• Sandra Tenreiro, CEDOC: Recovering neurofunction and promoting neuroprotection in diabetic retinopathy
• Dr. Wenjie Sun, Tulane University School of Public Health and Tropical Medicine, New Orleans, US, Lung inflammasome and lung cancer biomarkers.
• Mission Therapeutics – 1) Chemical probes for cancer therapies and diagnostics and 2) MS-based global drug profiling for novel cancer drugs.
• Dr. Manuel S. Rodriguez, France –A) Role of protein ubiquitylation in Mantle Cell Lymphoma resistance to Bortezomib (120 LC-MS runs), B) New insights into host-parasite ubiquitin proteomedynamics in P. falciparum infected red blood cells using TUBEs-MS approach (160 LC-MS runs) and C) Next generation Ubiquitin and SUMO traps.
• Professor David C Lyden and Ayuko Hoshino, Weill Cornell Medical College; Bruno Costa-Silva,Champalimaud, Lisbon; Henrik Molina, Rockefeller University – Exosome biomarkers.
• Dr. Carmen Rivas, Spain - PI3K signalling in cancer
• Professor Helena Viera and Prof. Miguel Viana-Baptista, director of Hospital São Francisco Xavier. Clinical trial for improving outcome and disclosing novel circulating biomarkers.
• Professor Margarida D. Amaral, EMBO chair and Dr. Carlos Farinha. Dissecting the endoplasmic reticulum quality control - differential protein interactions as new therapeutic targets in Cystic Fibrosis.
• Dr. Susana Seixas, researcher, IPATIMUP, Porto, Portugal and Felix Elortza LC-MS runs of infertile patients and controls (Proteogenomics).
• Dr. Sílvia Gomes, NGS sequencing of bronchoaviolar lavage microbiome.
• Dr. Paulo Matos, Targeting Rac1-signaling to enhance iodide-related therapy in breast cancer.
• Dr. Susana Lucas, COPD biomarkers
• MD Amélia Feliciano, kerman Aloria - OSA biomarkers
• Hans Christian Beck, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Denmark
• Dr. Maria Gomes da Silva, Haematology Unit, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.
• Dr. Antonio Bugalho, CUF, Lisbon
• Paula Borralho, CUF, Lisbon