Research Abstract
Maintaining proper tissue homeostasis involves careful regulation of cellular proliferation and survival in stem and transient amplifying cells. This is particularly true of the epidermis, which undergoes a constant process of proliferation, stratification, and differentiation. The epidermis is particularly susceptible to environmental damage, and unchecked proliferation of damaged cells can lead to cancer. Tumor suppressors such as p16INK4a and p53 serve the important function of causing growth arrest or apoptosis of damaged cells, but this has the unfortunate consequence of reducing normal tissue regenerative potential. In addition, there are many positive regulators of proliferation and stem cell function that when inappropriately activated can promote tumorigenesis. Thus, the combination of aberrant activation of normal growth regulators combined with the loss of tumor suppressors in epithelial tissues can lead to tumor development.
Squamous Cell Carcinoma (SCC) is a common cancer that develops in stratified epithelial tissues such as the epidermis, the oral cavity, and the lungs. While cutaneous SCC can usually be managed surgically, unresectable SCC has few effective treatments, resulting in more than 7,000 deaths every year. SCC tumors found in the head & neck region (HNSCC) and the lungs (Squamous NSCLC) have much poorer prognosis, as surgical options are often limited. Despite intense study, the current lack understanding of the molecular genetics of SCC has resulted in little progress in improving overall survival of overall survival of patients with HNSCC, squamous NSCLC, and aggressive cutaneous SCC. Therefore, it is essential to gain a better molecular understanding of the genetic events driving SCC in order to find new targets for treatment.
The Ramsey laboratory is focused on exploring the mechanisms that drive SCC, in order to develop more targeted and effective therapies. We use tissue-specific activation of driving oncogenes combined with inactivation of tumor suppressors to develop pre-clinical SCC models which contain genetic alterations seen in human SCC which can be used to test novel therapeutics and elucidate how specific combinations of lesions cause the development of SCC tumors. To complement this work, we have also developed a variety of biochemical systems to investigate the role of transcription factors and associated co-factors in driving SCC-specific transcription. These tools can be applied to study the large variety of transcription factors that contribute to the pathogenesis of SCC. Understanding the differences in transcriptional networks between normal and cancerous tissues will offer insight into the vulnerabilities of SCC tumors that can be therapeutically targeted to improve the survival and quality of life of patients.
