Cancer Stem Cells and Cell Plasticity

PEREZ CASTRO, CAROLINA; FERREYRA SOLARI, NAZARENA; BELFORTE, FIORELA SABRINA; CANEDO, LUCIA

CABA

Exposición; 1er SAB- Scientific Advisory Board; 2014

The main goal of our research activities is to characterize gene expression regulation in stem cells (SCs), including cancer stem cells (CSC), by TGF-β signaling, to elucidate the molecular mechanisms underlying SCs properties. We designed a novel bioinformatics algorithm (INSECT) that assists for the identification of transcription factor binding sites (TFBSs) and cis-regulatory modules (CRMs) for gene(s) of interest. In particular, we study genes (candidate genes) that might be under the co-regulation of the core transcriptional factors (Sox-2/Oct-4, Nanog) that confer stemness properties and the TGF-β/SMAD pathway. SCs can be propagated in vitro under conditions that promote self-renewal. The transcription factors Oct-4, Sox2 and Nanog constitute a ?core? to maintain self-renewal properties in pluripotent embryonic SCs. The activities of the TGF-β family members, i.e. TGF-β/Activin-like factors and bone morphogenetic proteins (BMPs) are potential regulators of SCs properties and cell fate decision, although, the underlying molecular mechanisms are not known in details. Many critical signaling pathways necessary for SCs identity are found activated in tumor cells, particularly in tumor cells called cancer initiation cells (CIC) or cancer stem cells (CSC). CSC share many characteristics of SCs, including self-renewal and potentiality for cell differentiation, which are considered to drive the metastasic behavior of cancer cells and to be responsible for tumor recurrence. We aim to study the molecular mechanisms involved in these cell plasticity processes and its possible relationship with cancer, as a result of their deregulation. By using our new bioinformatics tool (INSECT) we identified CRMs of genes potentially co-regulated by Core factors and SMADs proteins in embryonic SCs. Applying restrictions in the search parameters based on publication data, we found among the predicted genes, other novel genes not previously associated with the core transcription factors and/or modulated by TGF-β family proteins. Over 6000 genes, we selected 6 genes (3 genes orthologous human and murine), mainly chromatin regulators and signaling molecules and then we analyzed their expression levels (RT-qPCR) under the modulation by TGF-β signaling proteins. Based on this analysis we further engaged the biochemical and functional experiments in embryonic SCs and CSC.