The primary feature of tumor processes is the disruption of cellular homeostasis, caused by mechanisms like cell cycle deregulation, defective DNA repair, abnormal apoptosis, and impairments in protein localization and post-translational modifications. Our research group aims to define these mechanisms and their roles in malignant transformation, which could inform new therapeutic strategies for clinical applications.

We focus on molecular mechanisms that regulate cell homeostasis, structured into five main research lines:

Maintaining cellular homeostasis requires tight regulation of cell cycle progression, DNA repair, and apoptosis. E2F proteins (E2F1-8) are central transcriptional regulators of these processes, controlling numerous target genes through activation and repression. In various cancers, E2F dysregulation is common, contributing to tumor progression and serving as a hallmark of malignancy.

Our laboratory is currently focused on uncovering the mechanisms behind E2F1- and E2F7-mediated transcriptional repression. Using state-of-the-art approaches, including proximity proteomics, high throughput microscopy-based screenings, ChIP-seq, or ATAC-seq, we have identified several epigenetic regulators that interact with E2F1 or E2F7. Our goal is to define the functional role of these regulators in E2F-driven transcriptional repression during cell cycle progression and the DNA damage response, and explore their potential implications in cancer biology.

The metastatic process involves a transcriptional shift from a highly metabolic and proliferative state, ideally suited for the growth of the primary tumor, to a mesenchymal state associated with the acquisition of discreet competencies that lie beyond cell proliferation, and include cell motility, invasive capacity and upregulation of inflammatory pathways. Stemming from the notion that E2F factors are key regulators of cell proliferation and that their activity is commonly altered in cancer, the main goal of this research line is to unveil E2F-driven transcriptional networks governing cell plasticity and the acquisition of pro-metastatic features in cancer cells. To address our research questions, we apply cutting-edge techniques and models, including conditional knockout and xenograft animal models, colorectal cancer patient-derived organoids (PDOs), high-throughput microscopy-based RNAi screens, as well as genomic and proteomic approaches.

Despite significant progress in identifying E2F targets—primarily genes linked to DNA replication, repair, and G1/S transition—many still uncharted E2F target genes likely contribute to broader cellular functions. Mapping these genes and understanding their roles could provide deeper insights into the in vivo mechanisms of E2F activity. Our recent findings reveal that E2Fs regulate genes associated with organelle duplication, including those involved in Golgi apparatus biogenesis (e.g., GOLPH3) and centrosome duplication (TEDC1, TEDC2). We are currently conducting proteomic and super-resolution microscopy assays to further investigate the connections between the cell cycle and centrosome function, aiming to clarify how these interactions ensure accurate cell division and suppress neoplastic transformation.

Our recent findings have highlighted a novel role for E2F1 and E2F2 as negative regulators of immune responses, which may potentially impact inflammation and tumorigenesis. In the absence of E2F1/2 the immune system becomes hyperreactive, with E2f2-KO mice showing signs of autoimmunity, including inflammatory infiltrates in multiple organs and immune-mediated organ injury. Remarkably, our E2f knockout models exhibit resistance to tumor formation across several tumorigenesis models. To further explore the contribution of E2F on the tumor immune microenvironment and anti-inflammatory responses, we are currently employing a combination of genomic single-cell RNA sequencing (scRNA-seq) and animal models of tumorigenesis as well as systemic or tissue inflammation. This approach aims to provide insights into how E2F factors modulate immune activity within inflammatory and tumorigenic contexts.

Given their critical role in cell homeostasis, the function of E2F factors needs to be tightly regulated. Binding to the retinoblastoma (RB) protein is a key regulatory mechanism for most E2Fs. However, some members of the family, such as E2F7, are unable to bind RB and thus, other mechanisms, still largely unknown, must be involved in regulating their activity. We are investigating how E2F7 function is potentially regulated by active transport between the nucleus and cytoplasm and by ubiquitin-like post-translational modifications. We are using site-directed mutagenesis, gene editing, confocal microscopy and functional assays, in both in vitro and in vivo models to elucidate how these two key processes, contribute to modulate the function of E2F7.