Cell cycle regulation and tumor development
Our group is interested in deciphering the mechanisms by which cell cycle regulators mediate cellular proliferation and cell fate, including the dysregulations that contribute to oncogenesis and to tissue atrophy. We use a combination of transcriptomic and proteomic approaches together with diverse cellular and mouse models to investigate the relevance of the Retinoblastoma/E2F pathway in DNA metabolism, genome stability, and in the maintenance of quiescent and differentiated states in cells.
Our main lines of research:
1. Mechanisms governed by E2F factors to control DNA metabolism
We aim to explore the role that the E2F family of transcription factors has in the control of DNA metabolism in both normal and tumor cells. Our research group showed that E2F family members (E2F1, E2F2, E2F7) are essential for controlling DNA replication, repair and maintenance (Iglesias et al. 2010; Mitxelena et al. 2016, 2018). The finding of genomic instability after E2F depletion in mouse models and in tumor cell lines has allowed us to identify a set of E2F-regulated metabolic enzymes that supply the cell with precursors for DNA replication. We are currently characterizing in detail the transcriptional regulation of genes involved in DNA metabolism by E2F family members, including the identification of key regulatory sequences in gene promoters and detection of possible co-regulatory proteins. We are also studying the impact of over-expression of these genes in resistance to chemotherapy, and assessing novel approaches of inhibiting the activity of these E2F-target enzymes to be used as a therapeutic strategy in the treatment of cancer.
Role of E2F factors in the maintenance of differentiated phenotypes and suppression of mesenchymal traits
We have previously reported that E2F1 and E2F2 factors are critical for the maintenance of pancreatic homeostasis, and that targeted inactivation of these factors results in loss of pancreatic differentiation and in acquisition of mesenchymal traits (Iglesias et al, 2004, 2015). Our more recent data suggest that E2F1/E2F2 activity negatively controls EMT-like phenotypes, however, how E2F factors abrogate cell state changes and the impact of these novel functions of E2F1/E2F2 factors in cancer cell biology remains to be resolved. Some of the approaches to study this objective involve the characterization of well-established EMT and stemness features, the study of E2F1/E2F2-dependent transcriptional profiles that maintain the epithelial architecture and abrogate cell rewiring towards mesenchymal forms, the identification of locus-specific protein complexes associated with E2F1/E2F2 that mediate non-canonical E2F functions, and elucidating the contribution of E2F in modulating the tumorigenic potential.
Identification and characterization of novel E2F target genes
We are interested in identifying and characterizing novel E2F target genes of unknown function. A bioinformatic analysis has allowed us to identify several Open-Reading-Frames (ORFs) that are potentially regulated by E2Fs, and whose expression is correlated with cell division and cancer progression. We are currently analyzing the E2F-mediated transcriptional regulation of these ORFs, defining their interactors through proteomic screens, carrying out loss-of-function and gain-of function experiments to determine their biological functions, both in cell cultures and in mice, and characterizing the intracellular signaling pathways altered by overexpression of ORFs that contribute to tumorigenesis.