Using skin as an epithelial model system shows promise in shedding light on the development of cancer.
One of the contributors of cancer is the process of stem cells uncontrollably forming tissues. Because human and mouse stem cells in skin epithelium can be cultured, skin was chosen as the model system in the Fuchs lab at the Rockefeller University. With many opportunities for mutagens to come into contact with skin and change its regulation, it is important to understand how epithelial growth is regulated in development and cancer.
This past Tuesday, Slobodan Beronja, presented at a seminar sponsored by the Norris Cotton Cancer Center and the DMS Biochemistry Program. Beronja, a post-doctoral fellow in the Fuchs lab, used RNAi (RNA interference) in mouse skin to reduce the expression of genes in biological pathways to study the effect on the development of the epithelial layer. A lentiviral vector, which is capable of delivering genetic information to the host cell, was introduced into the mouse using ultrasound-guided intra-amniotic injections. By targeting genes involved in epithelial growth using RNAi, Beronja was able to recapitulate the knockout phenotype observed in tissues and in explants, or cells taken from pieces of tissues. For example, both RNAi and knockout of the gene Ctnna1 resulted in defects in the epidermis, suggesting that RNAi in mouse skin is an effective method for analyzing the functions of genes involved in the regulation of epithelial growth.
In addition to using RNAi in mouse skin, Beronja also conducted a genome-wide RNAi screen to identify physiological regulators of epithelial tissue growth during embryonic development. A Gene Ontology (GO) enrichment analysis was done to identify positive and negative regulators of oncogenic growth.
With regulators of oncogenic growth identified, further research will be done to understand the interactions between various factors and their contribution towards cancer. There are three approaches that Beronja may use to undertake this large project. First, a candidate-based analysis of gene function may be done to understand the roles of particular genes. In addition, a large-scale investigation of modifiers of epithelial tissue may be conducted. Beronja hopes to use this information to develop a general model using either mammary gland cells or airway epithelium, because of the common occurrences of breast cancer and lung cancer, respectively.