Inés Martín Barros
Inés Martín Barros
Cancer Cell Signaling And Metabolism Lab & Structural Biology of Cancer Lab
Address: Bizkaia Science and Technology Park, building 801A, Derio (Bizkaia)

The research in the Carracedo lab is aimed at deconstructing the essential requirements of cancer cells with special emphasis on the translation of the acquired knowledge from bench to bedside. In order to define the genuine features of cancer cells, we focus on the signalling and metabolic alterations in prostate and breast cancer. Through the use of a hierarchical approach with increasing complexity, we work on cell lines and primary cultures (using cell and molecular biology technologies), mouse models of prostate cancer that are faithful to the human disease and the analysis of human specimens through the development of prospective and retrospective studies. Our work stems from the hypothesis that cancer is driven by signalling and metabolic alterations that, once identified, can be targeted for therapy. The center and our collaborator institutions offer state-of-the-art technologies (from OMICS to in vivo imaging), which allow us to build and answer our hypotheses with high level of confidence.
To address our scientific questions in cancer, the Carracedo lab has developed a series of research lines:

  • Bioinformatics-based discovery. The lab takes full advantage on publicly available human prostate and breast cancer datasets in order to identify candidate genes to contribute to cancer pathogenesis, progression and response to therapy. Best hits are then validated employing genetic mouse models, xenograft surrogate assays and the latest advances in cellular and molecular biology combined with OMICs technologies.
  • Genetic mouse models as a source for the identification of novel cancer players. Genetically engineered mouse models (GEMMs) can faithfully recapitulate many aspects of human cancer. Dr. Carracedo envisions the molecular analysis of GEMMs with high throughput technologies as a mean to identify novel cancer-related genes. These hits are then validated through the analysis of human cancer specimens and cellular and molecular biology approaches.
  • Multi-OMICs analysis for non-invasive biomarker identification. Biofluids are the perfect source for cancer biomarkers that can inform about the presence or features of cancer. The lab has undertaken a biomarker discovery approach by applying the latest OMICs technologies to biofluid specimens from well-annotated prostate cancer patients, in order to define better molecules that inform about this disease.

The Structural Biology and Cancer Lab primarily uses NMR for biomolecular structural characterization and incorporates complementary structural and functional studies through collaborations. This integrative structural and functional approach is indispensable to understand protein complexes relevant in chromatin remodeling and DNA replication and repair. We study the INhibitor of Growth (ING1-5) family of tumor suppressors, which restrict cell growth and induce apoptosis through transcription regulation. They form interaction networks, binding histone H3 tails and recruiting Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC) complexes to the chromatin. The lab has characterized the structure of ING4 as a dimeric protein that recognizes histone H3 trimethylated at lysine 4 through its PlantHomeoDomain (PHD). Structure-sequence alignments suggest that homodimerization of other ING proteins, and even heterodimerization, may occur, especially between the highly homologous ING4 and ING5. The team is characterizing the structure of ING5 and its N-terminal domain, and the possible formation of heterodimers and also is studing the structural and functional implications of ING5 mutants detected in cancer. PCNA is a DNA sliding clamp, an essential factor for DNA replication and repair. It has a ring-shape structure and interacts with many proteins, including ING1. The group found by NMR that some interactions are extremely weak in solution, likely mediated by other factors in the cell. The PCNA associated factor p15 is overexpressed in cancer, with high levels correlating with poor prognosis, and becomes ubiquitylated upon DNA damage and also found that p15 is an intrinsically disordered protein that binds and threads through the PCNA channel with its N- and C-terminal tails remaining disordered at both sides of the ring. P15 binds simultaneously and independently to DNA, suggesting a regulation of PCNA sliding velocity on the DNA. This might facilitate the switch from replicative to translesion synthesis polymerase binding at stalled replication forks. The lab is investigating the structure and binding properties of ubiquitylated p15.