ICO - Germans Trias i Pujol
Josep Carreras Leukaemia Research InstituteDirections
Ctra de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona
Our research is focused on improving the understanding of the molecular mechanisms leading to T cell lymphomas appearance. We will develop our research by determining possible defective mechanisms during thymopoiesis and by developing preclinical mice models for the study of T cell lymphomas, such as angioimmunoblastic T cell lymphoma.
With this knowledge, we expect to design and validate new therapeutic treatments more specific and effective than the ones currently available, in order to improve patient’s survival and quality of life.
T cell lymphomas can be defined as a group of malignancies caused by the uncontrolled proliferation of T cells. They constitute less than 15% of all Non-Hodgkin's lymphomas and, within this group, frequency can vary enormously.
Despite all being caused by T cell defective cell growth, little is known about its specific origin. Besides, they present a wide variety of symptoms and clinical characteristics ranging from highly aggressive (fast-growing) lymphomas, to subtypes that can develop for years without endangering the patient's life (indolent); presence of enlarged spleen, liver and/or lymph nodes; eczema and skin rash appearance; age appearance and higher incidence in men than in women. As a result of this variability, it is often difficult to establish a correct diagnosis of the disease and even more difficult to design an appropriate therapy for its specific treatment.
Our line of research aims at improving our understanding of the molecular mechanisms leading to the defective behaviour of the T cells originating this type of lymphoma, to provide more specific and effective therapies to treat T cell lymphoma, improve the prognosis and quality of life of patients and, eventually, to find a cure.
Lines of research
- Characterisation of T cell lymphoma phenotype once the disease is developed, in order to find the specific T cell population inducing its appearance.
- Study thymocytes maturation processes and mature T cells response to antigens, to try to determine if lymphoma appearance can be already settled during thymopoiesis or once the T cells leave the thymus.
- Compare, using single cell sequencing technologies, the characteristics of defective thymocytes and T cells in mice models and try to find similarities in human patient’s samples and databases.
Show all publications
GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin's B lymphomas via NF-κB-dependent induction of HIF-1α.Leukemia May 2015, 29 (5) 1163-76.
Deregulated expression of glycolytic enzymes contributes not only to the increased energy demands of transformed cells but also has non-glycolytic roles in tumors. However, the contribution of these non-glycolytic functions in tumor progression remains poorly defined. Here, we show that elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), but not of other glycolytic enzymes tested, increased aggressiveness and vascularization of non-Hodgkin's lymphoma. Elevated GAPDH expression was found to promote nuclear factor-κB (NF-κB) activation via binding to tumor necrosis factor receptor-associated factor-2 (TRAF2), enhancing the transcription and the activity of hypoxia-inducing factor-1α (HIF-1α). Consistent with this, inactive mutants of GAPDH failed to bind TRAF2, enhance HIF-1 activity or promote lymphomagenesis. Furthermore, elevated expression of gapdh mRNA in biopsies from diffuse large B-cell non-Hodgkin's lymphoma patients correlated with high levels of hif-1α, vegf-a, nfkbia mRNA and CD31 staining. Collectively, these data indicate that deregulated GAPDH expression promotes NF-κB-dependent induction of HIF-1α and has a key role in lymphoma vascularization and aggressiveness.Más información
Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance.Cell Metab 3 Abr 2018, 27 (4) 828-842.e7.
Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8Más información
AIF-regulated oxidative phosphorylation supports lung cancer development.Cell Res Jul 2019, 29 (7) 579-591.
Cancer is a major and still increasing cause of death in humans. Most cancer cells have a fundamentally different metabolic profile from that of normal tissue. This shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis, termed Warburg effect, has long been recognized as a paradigmatic hallmark of cancer, supporting the increased biosynthetic demands of tumor cells. Here we show that deletion of apoptosis-inducing factor (AIF) in a KrasMás información
GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism.Cancer Cell 16 Sep 2019, 36 (3) 268-287.e10.
GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.Más información
Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.Science 5 Ene 2018, 359 (6371) 91-97. Epub 2 Nov 2017
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance ofMás información