Project proposal title: Role of dietary fatty acids in oral carcinoma metastasis
Principal Investigator: Coro Bescós Atin, MD PhD (VHIR)
Co-Principal Investigator: Salvador Aznar Benitah, PhD (IRB Barcelona)
Metastasis accounts for the vast majority of cancer-related deaths. For oral squamous cell carcinoma (OSCC), 50% of patients develop secondary lesions (mainly in lymph nodes and/or lungs) with a 40% overall survival rate. Therapeutic options for patients are limited, which translates into a clear unmet medical need. It is necessary to understand the mechanisms by which cells initiate and maintain metastatic growth to devise new OSCC treatments. We have recently identified which cells are uniquely responsible for the metastasis formation in OSCC, and they exhibit the following characteristics: i) they are exclusive in their ability to generate metastases; ii) they express the fatty acid translocase CD36, and express a unique lipid metabolic signature; iii) they directly link metastasis predisposition to dietary fat content; iv) they increase their metastatic initiation potency when treated with palmitic acid; v) they are highly sensitive to CD36 inhibition, which almost completely abolishes their metastatic potential in preclinical models (Pascual et al., Nature 2016). However, we still do not know the mechanism of action of CD36+ metastatic-initiating cells, and how extracellular free fatty acids and/or lipids contribute to metastatic progression in oral SCC. Here, we aim to uncover which fatty acids and/or lipids modulate metastatic stem cell functions and how they do it. To do so, we will combine human OSCC samples and metastatic orthotopic mouse models, with state-of-the-art quantitative transcriptomic, proteomic, metabolomic, and bioinformatic analyses to identify the effect of different dietary fatty acids in metastatic progression. We also aim at testing the effect of reducing the concentration of saturated fatty acids in the diet of patients with oral SCC, hence starting to translate our basic research results into the clinic.
Project proposal title: Cellular Senescense in Fibrosing Interstitial Lung Diseases
Principal Investigator: Jacobo Sellarés i Àlvar Agustí , MD PhD (IDIBAPS)
Manuel Serrano, PhD (IRB Barcelona)
Fibrosing interstitial lung diseases (ILDs) are a group of devastating diseases that have an unfavorable outcome, including idiopathic pulmonary fibrosis (IPF). In recent years, cellular senescence has been proposed as a mechanism that may be involved in lung fibrosis. This project seeks to explore cellular senescence in ILDs. Clinical, functional and radiographic data will be recorded from ILD patients visited at Hospital Clinic. Biological material (blood, bronchoalveolar lavage (BAL) and lung tissue biopsies) will be collected upon diagnosis and different senescence markers will be assessed. To assess the immune status of the host, we will characterize the immune infiltrate of the BAL, determine mRNA transcriptome and the concentration of soluble immune mediators in blood and BAL. A proteomic analysis by mass spectrometry will be performed in serum. The integration of results will be performed using a network analysis. This project has the potential to uncover clinically relevant mechanisms of cellular senescence in fibrosing ILDs and identify new therapeutic targets
Project proposal title: Metabolic Reprogramming as a Predictable Tool for Head and Neck Cancer Patients
Principal Investigator: Antonio Zorzano, PhD (IRB Barcelona)
Co-Principal Investigator: Matilde Lleonart, MD PhD (VHIR)
Currently, the acquisiton of resistance mechanisms is one of the most important issues in Oncology. While in general terms, a great majority of cancerous tissues decrease their proliferation due to apoptosis caused by radio – and chemotherapeutical regimes, most of them acquire novel mutations bypassing apoptosis to find novel niches to metastasize. Our laboratories and others, reported several years ago that cancer cells develop the ability to bypass mitochondrial function in order to avoid ROS accumulation. On the other hand, autophagy is a process tighly linked to the mitochondria which is altered in many diseases including cancer. In addition, autophagy inhibition is starting to be considered in clinical trials and autophagy plays a key role in the regulation of mitochondrial function. The final aim of this project will be to predict the therapeutic response of HNSCC patients accordingly to their metabolic reprogramming and autophagy integrity. For this purpose, at least 30 different cell lines derived from biopsies (HNSCC – head and neck cancer – patients) wil be collected and grown in culture to esstablish cell lines.
At metabolic level: ROS levels, mitochondrial respiration and function, glycolysis, amino acid utilization, apoptosis and autophagic pathways will be determined. These results will be correlated with the clinical and pathological characteristics of the patiens in order to determine if those patients which did not respond to conventional chemotherapeutical drugs have a higher de-regulation of metabolic reprogramming and/or autophagy.
Project proposal title: Targeting of BRAF mutant mRNA Alternative Splicing in Melanoma
Principal Investigator: Ana Arance, MD PhD (IDIBAPS)
Co-Principal Investigator: Juan Valcárcel, PhD (CRG)
After progressing to BRAFi+MEKi and immune-checkpoint inhibitors, BRAFmutant metastatic melanoma patients have no alternative therapeutic options. The combination or sequence of BRAFi+MEKi with splicing modulators may be effective to avoid or overcome resistance mediated by splice variants and that would lead to the development of clinical studies with this triple combination or in sequence after the development of splicing isoforms.
Acquired resistance to BRAF/MEK inhibitors is a clinical relevant issue for BRAF-mutant metastatic melanoma patients (pts). BRAF mRNA alternative splicing is a mechanism of resistance to targeted therapy.The aim of this study is to evaluate the impact of alternative splicing in patients treated with BRAF and MEK inhibitors and to assess the efficacy of splicing modulators in overcoming this resistance mechanism. The project has the potential to provide important new information about mechanisms of drug resistance in melanoma -a key medical problem- as well as to evaluate the potential of splicing inhibitors as a therapeutic approach in two groups of melanoma pts with different response kinetics.
Project proposal title: Epigenetic patterns of the adaptive immune system in kidney transplantion
Principal Investigator: Fritz Diekmann, MD PhD (IDIBAPS)
Co-Principal Investigator: Simon Heath, PhD (CNAG - CRG)
Whole genome sequencing highlighted the importance of epigenetics for the development of immune response in autoimmune diseases and cancer. Adaptive immune cell methylation pattern may be a fingerprint of acute rejection in kidney transplant recipients. We developed a study protocol for the analysis of phenotypic and methylation pattern of PBMCs from kidney transplant recipients.
The PhD4MD candidate will integrate a translational investigation team from IDIBAPS, working in strict collaboration with epigenetic bioinformatic experts from the CNAG-CRG.
Project proposal title: Connecting tumor heterogeneity and the tumor microenvironment
Principal Investigator: Santiago Ramon y Cajal, MD PhD (VHIR)
Co-Principal Investigator: Luis Serrano Pubul (CRG)
Besides all research efforts over the last decades, cancer remains the second leading cause of death worldwide. This can be in part addressed to the fact, that cancer is a complex disease which involves collaborating cell populations with various genetic alterations (tumor heterogeneity), which are further diversified by the nature of their micro environmental composition (tumor microenvironment).The proposed project therefore aims at determining the interplay between the heterogeneous tumor cells and the associated tumor environment.
Dissecting these interactions with a combination of cell-biology and systems biology approaches should allow uncovering the tissue specific control mechanisms that are defective in cancer. Ultimately, the reeducation of stromal cells to recover the control mechanisms responsible for normal tissue homeostasis might be an innovative strategy to support the current cancer treatments.
Project proposal title: Deep Phenotyping for assessing rare neurological disease NGS Data
Principal Investigator: Alfons Macaya Ruiz, MD PhD (VHIR)
Co-Principal Investigator: Sergi Beltran Agulló (CNAG-CRG)
Advances in genetics and biotechnology have revolutionized the diagnosis of rare neurological diseases (RND). Current case resolution with massive parallel sequencing reaches 20-40% of the cases, with higher figures in early-onset or multiorgan conditions. Our main goal in this project is to use NGS in identification of genetic causes of rare/ultrarare early-onset neurologic diseases, integrating “omics” platforms with systematic approaches to enrich and redefine phenotypic ontology in these conditions, allowing a comprehensive analysis of genomic data.
The URDcat (Undiagnosed Rare Disease Program of Catalonia) project aims to provide the Catalan Health System with personalized genomic medicine as a fully integrated service for patients with RND. The RD-Cat platform (rdcat.cnag.crg.eu), based on the RD-Connect platform (platform.rd-connect.eu), already contains deep and standardized clinical information from over 750 families and is expected to increase during the project. Only with the data being generated, the RD-Cat platform will contain almost 1,000 exomes and genomes before the end of the project. 400 of the exomes/genomes have already been analyzed. As a result, a massive amount of omics data is currently being generated which will be difficult to exploit using solely bioinformatic criteria. Given the uniqueness of the clinical features, it stands to reason that an improved annotation of these features (deep phenotyping) as well as an interpretation of the genomic variants based on the existing knowledge associated with such clinical data should improve our diagnostic rate.