Pilar Blancafort

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Research Interests

• Mechanisms of tumorigenesis and tumor progression
• Anti-cancer therapies

Research Synopsis

The goal of our laboratory is to investigate mechanisms of tumorigenesis and tumor progression, and to apply genome-wide techniques to develop anti-cancer therapies. Our research focuses on transcriptional regulation of gene expression during stem cell self-renewal and differentiation and during tumorigenesis. Tumor cells acquire malignant behavior by altering many signaling pathways. Dysregulation of gene transcription plays a pivotal role in generating phenotypic plasticity. For example, epithelial tumors are able to re-activate embryonary genetic programs, which allow tumor cells to migrate and disseminate. The diversity of transcriptional aberrations in cancer poses a basic obstacle to successful therapies, which would require simultaneous targeting of many pathways. The strategy that my laboratory has adopted takes advantage of tumor cell regulatory networks. First, we use artificial transcription factors (ATFs) as genetic probes to identify genes and gene pathways responsible for the appearance of specific malignant phenotypes. Second, we investigate the ability of ATFs to interfere with tumor cell regulatory programs. Cancer cell reprogramming with such artificial “genetic switches” may afford a new therapeutic strategy. In its simplest design, an ATF is composed of a DNA binding domain (DBD) and an effector domain (activator or repressor). A variety of molecular scaffolds have been used as DBDs, from chemical molecules to natural protein domains. One of the ATF scaffolds that we use is based on the Cys2-His2 zinc finger (ZF) domain. We have constructed multi-finger proteins specifically recognizing consecutive triplets of DNA by linkage of several sequence-specific ZF domains. When directed to specific DNA sequences in targeted promoters, ATFs can regulate endogenous genes involved in tumor progression. We also use large libraries of ATFs made by recombination of highly specific ZF domains to regulate cancer cell behavior. Additionally, the functional screens of ATFs in cancer cells aim to identify novel targets of neoplastic disease progression. We expect that ATF screens will provide functional insights and experimental validation of markers associated with poor clinical outcome. (Figure of Zinc Finger.)

Publications

Click above for PubMed publications.

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