WNT Oncogenic Transcription Requires MYC Suppression of Lysosomal Activity and EPCAM Stabilization in Gastric Tumours.

BACKGROUND AND AIMS: WNT signaling is central to spatial tissue arrangement, regulating stem cell activity, and represents the hallmark of gastrointestinal cancers. While its role in driving intestinal tumors is well characterized, WNT's role in gastric tumorigenesis remains elusive. METHODS: We have developed mouse models to control the specific expression of an oncogenic form of B-CATENIN in combination with MYC activation in Lgr5+ cells of the gastric antrum. We used multi-omics approaches applied in vivo and in organoid models to characterize their cooperation in driving gastric tumorigenesis. RESULTS: We report that constitutive B-CATENIN stabilization in the stomach has negligible oncogenic effects and requires MYC activation to induce gastric tumour formation. While physiologically low MYC levels in gastric glands limit B-CATENIN transcriptional activity, increased MYC expression unleashes the WNT oncogenic transcriptional program, promoting B-CATENIN enhancer invasion without a direct transcriptional cooperation. MYC activation induces a metabolic rewiring that suppresses lysosomal biogenesis through mTOR and ERK activation and MiT/TFE inhibition. This prevents EPCAM degradation by macropinocytosis, promoting B-CATENIN chromatin accumulation and activation of WNT oncogenic transcription. CONCLUSION: Our results uncovered a new signaling framework with important implications for the control of gastric epithelial architecture and WNT-dependent oncogenic transformation.

ENABLE 2017, the First European PhD and Post-Doc Symposium. Session 2: The OMICS Revolution.

The European Academy for Biomedical Science (ENABLE) is an initiative funded by the European Union Horizon 2020 program involving four renowned European Research Institutes (Institute for Research in Biomedicine-IRB Barcelona, Spain; Radboud Institute for Molecular Life Sciences-RIMLS, The Netherlands; Novo Nordisk Foundation Center for Protein Research-NNF CPR, Denmark; European School of Molecular Medicine-SEMM, Italy) and an innovative science communication agency (Scienseed). With the aim of promoting biomedical science of excellence in Europe, ENABLE organizes an annual three-day international event. This gathering includes a top-level scientific symposium bringing together leading scientists, PhD students, and post-doctoral fellows; career development activities supporting the progression of young researchers and fostering discussion about opportunities beyond the bench; and outreach activities stimulating the interaction between science and society. The first European PhD and Post-Doc Symposium, entitled "Breaking Down Complexity: Innovative Models and Techniques in Biomedicine", was hosted by the vibrant city of Barcelona. The scientific program of the conference was focused on the most recent advances and applications of modern techniques and models in biomedical research and covered a wide range of topics, from synthetic biology to translational medicine. Overall, the event was a great success, with more than 200 attendees from all over Europe actively participating in the symposium by presenting their research and exchanging ideas with their peers and world-renowned scientists.

ENABLE 2017, the First European PhD and Post-Doc Symposium. Session 1: Building the Foundations of Biology: Synthetic and Cellular Research.

The European Academy for Biomedical Science (ENABLE) is an initiative funded by the European Union Horizon 2020 program involving four renowned European Research Institutes (Institute for Research in Biomedicine—IRB Barcelona, Spain; Radboud Institute for Molecular Life Sciences—RIMLS, the Netherlands; Novo Nordisk Foundation Center for Protein Research—NNF CPR, Denmark; European School of Molecular Medicine—SEMM, Italy) and an innovative science communication agency (Scienseed). With the aim of promoting biomedical science of excellence in Europe, ENABLE organizes an annual three-day international event. This gathering includes a top-level scientific symposium bringing together leading scientists, PhD students, and post-doctoral fellows; career development activities supporting the progression of young researchers and fostering discussion about opportunities beyond the bench; and outreach activities stimulating the interaction between science and society. The first European PhD and Postdoc Symposium, entitled “Breaking Down Complexity: Innovative Models and Techniques in Biomedicine”, was hosted by the vibrant city of Barcelona. The scientific program of the conference was focused on the most recent advances and applications of modern techniques and models in biomedical research and covered a wide range of topics, from synthetic biology to translational medicine. Overall, the event was a great success, with more than 200 attendees from all over Europe actively participating in the symposium by presenting their research and exchanging ideas with their peers and world-renowned scientists.

ENABLE 2017, the First EUROPEAN PhD and Post-Doc Symposium. Session 4: From Discovery to Cure: The Future of Therapeutics.

The EUROPEAN ACADEMY FOR BIOMEDICAL SCIENCE (ENABLE) is an initiative funded by the European Union Horizon 2020 program involving four renowned European Research Institutes (Institute for Research in Biomedicine-IRB Barcelona, Spain; Radboud Institute for Molecular Life Sciences-RIMLS, the Netherlands; Novo Nordisk Foundation Center for Protein Research-NNF CPR, Denmark; European School of Molecular Medicine-SEMM, Italy) and an innovative science communication agency (Scienseed). With the aim of promoting biomedical science of excellence in Europe, ENABLE organizes an annual three-day international event. This gathering includes a top-level scientific symposium bringing together leading scientists, PhD students, and post-doctoral fellows; career development activities supporting the progression of young researchers and fostering discussion about opportunities beyond the bench; and outreach activities stimulating the interaction between science and society. The first European PhD and Postdoc Symposium, entitled "Breaking Down Complexity: Innovative Models and Techniques in Biomedicine", was hosted by the vibrant city of Barcelona. The scientific program of the conference was focused on the most recent advances and applications of modern techniques and models in biomedical research and covered a wide range of topics, from synthetic biology to translational medicine. Overall, the event was a great success, with more than 200 attendees from all over Europe actively participating in the symposium by presenting their research and exchanging ideas with their peers and world-renowned scientists.

ENABLE 2017, the First EUROPEAN PhD and Post-Doc Symposium. Session 3: In Vitro to In Vivo: Modeling Life in 3D.

The EUROPEAN ACADEMY FOR BIOMEDICAL SCIENCE (ENABLE) is an initiative funded by the European Union Horizon 2020 program involving four renowned European research institutes (Institute for Research in Biomedicine-IRB Barcelona, Spain; Radboud Institute for Molecular Life Sciences-RIMLS, the Netherlands; Novo Nordisk Foundation Center for Protein Research-NNF CPR, Denmark; European School of Molecular Medicine-SEMM, Italy) and an innovative science communication agency (Scienseed). With the aim to promote biomedical science of excellence in Europe, ENABLE organizes an annual three-day international event. This gathering includes a top-level scientific symposium bringing together leading scientists, PhD students, and post-doctoral fellows; career development activities supporting the progression of young researchers and fostering discussion about opportunities beyond the bench; outreach activities stimulating the interaction between science and society. The first European PhD and Postdoc Symposium, entitled "Breaking Down Complexity: Innovative models and techniques in biomedicine", was hosted by the vibrant city of Barcelona. The scientific program of the conference was focused on the most recent advances and applications of modern techniques and models in biomedical research and covered a wide range of topics, from synthetic biology to translational medicine. Overall, the event was a great success, with more than 200 attendees from all over Europe actively participating in the symposium by presenting their research and exchanging ideas with their peers and world-renowned scientists.

Gene context analysis reveals functional divergence between hypothetically equivalent enzymes of the purine-ureide pathway.

A major problem of genome annotation is the assignment of a function to a large number of genes of known sequences through comparison with a relatively small number of experimentally characterized genes. Because functional divergence is a widespread phenomenon in gene evolution, the transfer of a function to homologous genes is not a trivial exercise. Here, we show that a family of homologous genes which are found in purine catabolism clusters and have hypothetically equivalent functions can be divided into two distinct groups based on the genomic distribution of functionally related genes. One group (UGLYAH) encodes proteins that are able to release ammonia from (S)-ureidoglycine, the enzymatic product of allantoate amidohydrolase (AAH), but are unable to degrade allantoate. The presence of a gene encoding UGLYAH implies the presence of AAH in the same genome. The other group (UGLYAH2) encodes proteins that are able to release ammonia from (S)-ureidoglycine as well as urea from allantoate. The presence of a gene encoding UGLYAH2 implies the absence of AAH in the same genome. Because (S)-ureidoglycine is an unstable compound that is only formed by the AAH reaction, the in vivo function of this group of enzymes must be the release of urea from allantoate (allantoicase activity), while ammonia release from (S)-ureidoglycine is an accessory activity that evolved as a specialized function in a group of genes in which the coexistence with AAH was established. Insights on the active site modifications leading to a change in the enzyme activity were provided by comparison of three-dimensional structures of proteins belonging to the two different groups and by site-directed mutagenesis. Our results indicate that when the neighborhood of uncharacterized genes suggests a role in the same process or pathway of a characterized homologue, a detailed analysis of the gene context is required for the transfer of functional annotations.