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Marie Curie Actions-cofund (MCA-cofund)

Título: CAD_FL: Revealing the functional mechanism of CAD and its potential as a therapeutic target
Referencia: 608765
Investigador Principal: Moreno Morcillo, María
Fecha Inicio: 4/1/2015
Fecha Fin: 3/31/2018
Presupuesto Otorgado: 87.343,80 €
Fuente de Financiación: WHRI-ACADEMY PROGRAMME. 7 FRAMEWORK PROGRAMME (2007-2013)

Resumen:

Pyrimidine nucleotides are essential building blocks for DNA or RNA synthesis. In mammals, two possible routes entail the production of pyrimidines: nucleotides can be recycled by salvage pathways or synthesized de novo from small metabolites. In general, the activity of the latter is low in resting or fully differentiated cells but indispensable in proliferating cells. Thus, in tumour and neoplastic cells the de novo pyrimidine biosynthesis is invariably up-regulated in order to cover the elevated requirement of nucleic acids precursors. Pyrimidine biosynthesis through this pathway is initiated and controlled by CAD, a multifunctional protein that assembles into hexamers of ~1.5 MDa and catalyses the first three reactions of the process. Recently, the host laboratory determined the crystal structures of two fragments of human CAD, the DHO and ATC domains, the latter isolated or bound to the anti-tumoral drug PALA. These two pieces are of great interest but insufficient to understand the puzzling structure/function of the entire CAD particle, which contains two additional uncharacterized regions, the GLN and CPS domains. This project aims to decipher the structure of full-length CAD and to understand the catalytic and regulatory mechanisms that controls the biosynthesis of pyrimidines. The acquired knowledge will be used for rational design of compounds that could potentially modulate the activity of this multifunctional complex with the prospect of developing new and more potent anti-tumoral drugs.

Marie Curie Actions-cofund (MCA-cofund)

Título: ADIPOMET: Analyzing the crosstalk of tumor and adipose tissue during metastasis
Referencia: 608765
Investigador Principal: Peinado Selgas, Héctor
Fecha Inicio: 1/1/2016
Fecha Fin: 12/31/2018
Presupuesto Otorgado: 87.343,80 €
Fuente de Financiación: WHRI-ACADEMY PROGRAMME. 7 FRAMEWORK PROGRAMME (2007-2013)

Resumen:

Over the past several decades, incidences of overweight and obesity have been rising very rapidly. Similarly, the prevalence of malignant cancers is also rising in nearly all countries. Obesity has been associated to the increased risk to develop metastasis in certain cancers such as melanoma, colon, breast and ovary. It is necessary to understand the biological processes linking obesity to tumor progression. Metastasis is associated with poor prognosis in most of the cancer types; approximately 15–20% of melanoma patients will develop metastasis. Our preliminary results suggest that exosomes secreted by melanoma cells serve as novel communication mechanism between the tumor and the adipose tissue. In this proposal we plan, #1, to visualize and characterize the mechanism of exosome crosstalk between tumor cells and adipocytes. This will be followed by detailed studies of the functional consequences regulating melanoma invasion and metastasis. We will expand these studies with a detailed lipidomic analysis of adipocyte secretome during melanoma metastasis. #2 we will build on preliminary results showing that adiponectin levels in circulating exosomes are reduced in stage IV melanoma patients. After determining the contribution melanoma to downregulate the expression of adiponectin in the adipose tissue we will follow with experiments to determine what factor(s) regulate adiponectin secretion and the mechanism(s) by which adiponectin affects invasion and metastasis. We ultimately aim to generate the signatures of circulating exosomes in melanoma patients. We will correlate the number of circulating exosomes with BMI and metastatic risk determining lipidomic signatures to build rational therapies that can interfere with the metabolic pathways regulated during metastasis.

Marie Curie Actions-cofund (MCA-cofund)

Título: STEM-PSO: Unraveling the contribution of Epidermal and Non-Epidermal Progenitor cells in the development of Psoriasis
Referencia: 608765
Investigador Principal: Gago López, Nuria
Fecha Inicio: 1/1/2016
Fecha Fin: 12/31/2018
Presupuesto Otorgado: 87.343,80 €
Fuente de Financiación: WHRI-ACADEMY PROGRAMME. 7 FRAMEWORK PROGRAMME (2007-2013)

Resumen:

Skin is one of the most regenerative organs in adult mammals. Normal skin is a self-renewal tissue that maintains homeostasis due to the presence of epidermal progenitor cells (EPC). EPCs possess enormous proliferative potential, which is engaged at a slow basal rate throughout an individual’s lifespan, with upregulated cell division occurring during wound healing and some inflammatory conditions. However, the efficiency of their regenerative potential to sustain homeostasis under chronic inflammatory conditions such as psoriasis is not fully understood. In addition, whether non-epidermal progenitors (non-EPC) contribute to this process has not yet defined. Psoriasis is a chronic disease of unsolved pathogenesis affecting skin and joints in 1-3% of the general population. It is known EPC derived human transitamplifying (TA) keratinocytes exhibit an increased proliferation, but a reduced apoptotic rate in psoriatic plaques, fostering epidermal hyperproliferation and altered differentiation.

Whether this disarray in the balance of proliferation-apoptosis stems from EPCs and derived TA keratinocytes, or is that other cells, such as non-EPCs, could potentially be recruited to psoriatic plaques and contribute to nourish the disease is unknown. Further research and the development of innovative approaches are therefore needed to get insight into this problem, which in addition will have a potential impact in the future design of improved molecular and cell therapies.

The main goal of this proposal is to study the contribution of EPCs and non-EPCs in the formation of psoriatic plaques through a genetic fate-mapping approach, analyze the molecular signals involved in the uncontrolled proliferation/differentiation/apoptosis of these keratinocytes and translate these results to human patients in situ and in vitro.

Marie Curie Actions-cofund (MCA-cofund)

Título: NFIC as a novel regulator of pancreatic acinar differentiation and homeostasis
Referencia: 608765
Investigador Principal: Sumit Paliwal
Fecha Inicio: 11/20/2017
Fecha Fin: 12/31/2018
Presupuesto Otorgado: 41.471,67 €
Fuente de Financiación: WHRI-ACADEMY PROGRAMME. 7 FRAMEWORK PROGRAMME (2007-2013)

Resumen:

Transcriptional regulators are key to tissue homeostasis and recovery from damage. In pancreatic acinar cells, the PTF1 complex acts in concert with other transcription factors to support acinar cell identity. One of them is Nr5a2 that is crucially required to prevent pancreatic inflammation. Moreover, SNPs in the vicinity of NR5A2 are associated with the risk of developing pancreatic cancer. Work from the host lab has identified nuclear factor I/C (Nfic) as a novel interacting partner of Nr5a2. This proposal focuses on investigating the role of Nfic in pancreas physiology and disease. To accomplish this, I propose to analyze: 1) the effects of Nfic inactivation on pancreatic morphology and exocrine function by performing a time-course analysis of histology and expression changes in pancreas-specific transcription factors along with their cognate target genes using Nfic knockout mice; 2) the recovery from acute and chronic caeruleininduced pancreatitis in wild type and Nfic-null mice using quantitative histology, immunohistochemistry and RT-qPCR; 3) the genomic distribution of Nfic in pancreatic cells and its relationship with the genome binding of other transcriptional regulators involved in pancreatic differentiation by performing ChIP-Seq; and 4) the relevance of Nfic to human cancer by mining public databases (TCGA, ICGC and others) and by crossing the Nfic knockout mice with Ptf1a-Cre:KrasG12V mice to examine its role in tumour development and progression. If our data support a key role for Nfic in the pancreas, we will generate a pancreas-specific conditional knockout of Nfic in order to determine which aspects of the phenotype are epithelial vs. onepithelial cell autonomous.

Marie Curie Actions-cofund (MCA-cofund)

Título: Structure-Function studies of oncogenic RET kinase Fusions in non-small cell Lung Cancer (NSCLC): from structure to targeted therapy
Referencia: 608765
Investigador Principal: Plaza Menacho, Iván
Fecha Inicio: 10/1/2017
Fecha Fin: 12/31/2018
Presupuesto Otorgado: 46.562,5 €
Fuente de Financiación: WHRI-ACADEMY PROGRAMME. 7 FRAMEWORK PROGRAMME ( 2007-2013 )

Resumen:

Lung cancer is the leading cause of cancer deaths in the world, accounting for more solid tumor deaths than breast, pancreatic, prostate and colorectal cancers combined. Despite such strong incidence, paradoxically it is an understudied type of cancer compared to others. The recent identification of oncogenic RET kinase fusions KIF5B-RET and CCDC6-RET in NSCLC has directed attention to RET as a new therapeutic target in lung cancer. In unselected populations of NSCLC patients, RET fusions are present in 1-2% of cases.

However, this incidence increases substantially up to 16-17% in never-smoker’s cases lacking other known oncogenic alteration, potentially defining an exclusive molecular subtype (Drilon et al., 2013; Kohno et al., 2013). This basic to translational research program will give insights into the mechanisms of action associated with KIF5B-RET and CCDC6-RET oncogenic fusion in lung cancer at the atomic and molecular levels. Crucially, current compounds targeting RET kinase activity that are tested in the clinic are not specific, mainly due to lack of early drug-discovery projects specifically focused on RET. The mechanistic insights provided by our structure-function studies will be further translated into the design and development of more potent and specific RET kinase inhibitors, both ATP-competitive and allosteric compounds, potentially leading to better and more successful personalized-based therapies in the near future.

Marie Curie Actions-individual Fellowship (MCA-IF)

Título: PERSMEDOMICS: Bioinformatics and Integrative Genomics for a Novel Personalized Cancer Therapy
Referencia: 334361
Investigador Principal: Al-Shahrour Núñez, Fátima
Fecha Inicio: 7/1/2013
Fecha Fin: 6/30/2017
Presupuesto Otorgado: 100.000,00 €
Fuente de Financiación: 7 FRAMEWORK PROGRAMME (2007-2013)

Resumen:

The dawn of the age of personalized cancer treatment provides the promise to identify the right drug for the individual that will greatly improve the patient’s outcome. It is well known that cancer drugs work only in small subset of patients. For many of these agents, there are putative markers of response in the literature but very few are been used in clinical practice. More importantly, new anticancer agents are targeted to specific cancer genes and are expected to be effective only in tumors in which these genes are mutated or otherwise abnormal. Consequently, the success of personalized treatment of cancer patients depends on matching the most effective therapeutic regimen with the characteristics of the individual patient, balancing benefit against risk of adverse events. The primary challenge in achieving this goal is the heterogeneity of the disease, recognizing that breast, lung, colon and the majority of cancers are not single diseases but rather an array of disorders with distinct molecular mechanisms.

High-throughput technologies such as next-generation sequencing, gene expression microarrays have the capacity to dissect this heterogeneity and now doing an unbiased interrogation of the human genome, which allows strategies to search for novel, previously unsuspected, biomarkers of drug response and afford opportunities to match therapies with the characteristics of the individual patient’s tumor.

Here we propose to develop an integrative bioinformatics approach as part of CNIO’s personalized cancer treatment platform that will predict treatment response and select new biomarkers based on the integration of genomics data and drug response analyzed in patients with pancreatic cancer and personalized xenografted mice. A cross-disciplinary integrative effort that will convert the information contained in multidimensional data sets into useful biomarkers that can classify patient tumors by prognosis and response to therapeutic modalities.

Marie Curie Actions-individual Fellowship (MCA-IF)

Título: GLIDD: DNA Damage Response (DDR) signaling in tumor formation and therapeutic resistance of gliomas
Referencia: 618751
Investigador Principal: Squatrito, Massimo
Fecha Inicio: 7/1/2014
Fecha Fin: 6/30/2018
Presupuesto Otorgado: 100.000,00 €
Fuente de Financiación: 7 FRAMEWORK PROGRAMME (2007-2013)

Resumen:

The gliomas are a large group of brain tumors and Glioblastoma Multiforme (GBM) is the most common and lethal primary central nervous system (CNS) tumor in adults. Despite the recent advances in treatment modalities, GBM patients generally respond poorly to all therapeutic approaches and prognosis remain dismal. Standard therapy for GBMs includes resection of the tumor mass, followed by concurrent radiotherapy and chemotherapy, using the alkylating agent temozolomide (TMZ). Nonetheless, GBM patients remain refractory to treatment. Understanding the genetic events that lead to glioma formation and the mechanisms of resistance to therapy will be instrumental for the development of new treatment modalities for gliomas.

Maintenance of genomic integrity is essential for embryonic development and adult tissue homeostasis. Defects in the DNA Damage Response (DDR) machinery, a network of protein complexes capable of detecting DNA lesions and signaling to downstream effector pathways (cell cycle checkpoints, DNA repair, apoptosis, etc.), are linked to numerous pathological states including brain cancers. The focus of this proposal is the identification of DDR genes involved in tumor formation and therapy resistance of gliomas. We will also investigate how the tumor microenvironment contributes to resistance to standard treatment modalities. We reason that these studies will help to define new therapeutic targets for treatment of brain tumors.

Marie Curie Actions-inovative Training Networks (MCA-ITN)

Título: ITN aDDRess: Joint training and research network on Chromatin Dynamics and the DNA Damage Response
Referencia: 316390
Investigador Principal: Fernández-Capetillo, Oscar
Fecha Inicio: 10/1/2012
Fecha Fin: 9/30/2016
Presupuesto Otorgado: 3.804.294,12 €
Fuente de Financiación: 7 FRAMEWORK PROGRAMME (2007-2013)

Resumen:

DNA is tightly wrapped around histones to form chromatin, a highly dynamic structure that can adopt different conformations with contrasting degrees of compaction. Essential processes of DNA metabolism, such as DNA repair, replication or transcription operate in the context of chromatin and higher order chromosomal organization. Understanding how modulation of chromatin structure and repair influence cell fate decisions in development and disease or how genome surveillance factors interact with the chromatin structure to safeguard the genome is an emerging question that represents a major challenge for human health. The objectives of the aDDRess ITN are: 1. to establish a European research platform of excellence in the proposed field, 2. to create a Network dedicated for the training of ESR/ERs promoting their independent careers and prospects and 3. to transform our current collaborations into a stronger intellectual and training network with links to the industry. In addressing these aims, we have put forward a multidisciplinary approach to study this central thematic area at the molecular, cellular and systems level by assembling a group of scientists with cross disciplinary expertise and capabilities. This integrated approach is likely to provide a solid groundwork on genome maintenance and chromatin dynamics driven by DNA damage.

Marie Sklodowska Curie Actions-inovative Training Networks (MSCA-ITN)

Título: INMUTRAIN: Training Network for the Immunotherapy of Cancer
Referencia: 641549
Investigador Principal: Soengas González, María Soledad
Fecha Inicio: 6/13/2016
Fecha Fin: 6/12/2019
Presupuesto Otorgado: 3.627.525,24 €
Fuente de Financiación: HORIZON 2020 (2014-2020)

Resumen:

In the European Union, cancer is the leading cause of death and the overall cancer incidence is still increasing. As a result of expanding efforts to improve cancer outcome, a main paradigm change is occurring in cancer therapy towards individualized medicine. Antibody-based therapies form an integral and constantly growing part of this approach. Antibody-based therapies will strongly influence the coming decade of cancer care. The importance of immunotherapy has been highlighted by the prestigious Science journal as “breakthrough of the year 2013”, heralding the rising importance of immunotherapy. Accordingly the need for well-trained and skilled researchers in academia and industry is dramatically increasing in this field. IMMUTRAIN is a training network bringing together experts in the fields of monoclonal antibodies, dendritic cells, T-cells and immunomodulatory nucleic acids with a considerable industrial involvement. The network comprises nine academic research groups and five industrial partners in a total of seven European countries. IMMUTRAIN will actively create synergies between those sectors by forming and promoting young researchers to match the challenges of immunotherapies. Particular focus will be placed on combinatorial therapies and on the new emerging field of bispecific antibodies used to target both the tumor and the patient´s immune system. Fifteen Ph. D. students (early stage researchers, ESR) reinforced by the project leaders will investigate innovative therapeutic strategies and provide the rationale for future clinical trials. Throughout their projects, ESR will learn to integrate academic and industrial aspects and will sharpen their experimental and complementary skills in a well-designed and diversified training program.

Marie Sklodowska Curie Actions-individual Fellowships (MSCA-IF)

Título: METMEL: Long range-acting drivers of premetastatic niches in melanoma
Referencia: 753442
Investigador Principal: Frago Moreno, Susana
Fecha Inicio: 4/1/2017
Fecha Fin: 3/31/2019
Presupuesto Otorgado: 170.121,6 €
Fuente de Financiación: HORIZON 2020 (2014-2020)

Resumen:

Melanoma is the cancer with the fastest rising incidence world-wide, and although recent therapies can achieve unprecedented response rates, a significant fraction of patients still succumb to metastatic lesions. Key pending questions in the field are the mechanisms underlying the inherent metastatic behaviour or melanoma, whereby seemingly thin primary lesions (≥2 mm in depth) bear high risk of dissemination to proximal lymph nodes and ultimately, to distal sites. A dynamic crosstalk has been proposed to be established between melanoma cells and the lymphatic vasculature at tumour-draining lymph nodes, favouring an immune-permissive “lymphovascular niche”. However, whether (and how) these lymphovascular interactions occur at distal sites is unclear. The Soengas group has generated unique “Lymphoreporter” melanoma mouse models for non-invasive and whole body imaging of tumour progression. These lymphoreporters demonstrated that primary melanomas induce neo-lymphangiogenesis at distal pre-metastatic sites, already from very early stages of the disease,

before dissemination occurs. Proteomic analyses were then performed to identify factors in the melanoma secretome that could drive these long range-acting effects and subsequently filtered these proteins for novelty (i.e. no previous link to melanoma and lymphangiogenesis). Here we will focus on the top-ranking factors in this screening. In particular, we will define the impact of these newly-identified melanoma secreted factors on tumour progression and metastasis, focusing on key components of the lymphovascular niche (i.e. on the crosstalk of tumour- vasculature-immune system). Secondly, we will assess the impact of these genes as prognostic biomarkers and indicators of response to clinically-relevant treatments.

These studies will be performed in collaboration with dermatologists, pathologists and oncologist to define the physiological relevance of our work.

Marie Sklodowska Curie Actions-individual Fellowships (MSCA-IF)

Título: METLINK: Identification of links between cancer cell growth and metabolism genes
Referencia: 794177
Investigador Principal: Zauri, Melania
Fecha Inicio: 10/1/2018
Fecha Fin: 9/30/2020
Presupuesto Otorgado: 158.121,6 €
Fuente de Financiación: HORIZON 2020 (2014-2020)

Resumen:

Metabolism is crucial for cellular survival. The large amount of evidence covering metabolic entries is mainly about the enzymatic processes and single reactions happening within the metabolic map, but there is poorer understanding of the cellular growth signaling network and regulation around metabolism. With METLINK we aim at identifying new and previously undiscovered selective links between metabolic genes and cellular growth pro-survival mechanisms. The hits will be identified with the use of a pooled libraries of CRISPR/Cas9 lentiviral vectors against metabolic genes and cell cycle/cancer genes. The metabolic library targets will be divided into sub-pools (carbohydrate metabolism: 245; inositol metabolism and lipid metabolism: 571; tricarboxylic acid (TCA) cycle, respiratory chain, integration energy metabolism: 240; nucleotide metabolism, vitamin synthesis and biological oxidations: 361; amino acid metabolism and protein processing: 667; others: 355) and therefore be amenable to medium-throughput screening and selected metabolic processes interrogation. The cancer/cell cycle genes target will be approximately 500 genes. The screening will be initially performed on the human fibroblasts BJ and IMR90, easier to genetically modify, and later validated in other relevant cancer cell line. This will result in the identification of new Achilles’ heels in cancer within metabolism and propose new druggable targets. They will be validated and screened with a library of compounds actually present at SciLifeLab within Karolinska Institute. Lately this proposal will elucidate potential links between oncogenes or cellular growth genes and metabolic genes providing new avenues for treatment within metabolic reactions.

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