- Signal transduction in transformation and adipocytic differentiation. a) Ras, b) Stat3
- Electroporation of adherent cells in situ
Details of Research Interests:
Cellular interactions with neighbouring cells profoundly influence a variety of signalling events involved in mitogenesis, survival and differentiation. Unlike tissue-culture cells, cells in a tumor have extensive opportunities for adhesion to their neighbours in a three-dimensional structure, therefore in the study of these processes it is important to take into account the effect of surrounding cells. Cadherins recently emerged as a group of cell-cell adhesion molecules playing a key role in the regulation of signalling events as well as the maintenance of tissue architecture.
Our lab has recently demonstrated that engagement of E-cadherin can lead to a dramatic increase in the activity of Stat3, a protein often abnormally activated in cancer. Most importantly, Stat3 activation was independent from a number of tyrosine kinases, including the Src family, IGF1-R, EGFR and Fer, often activated in many cancers. This novel pathway could be a promising target in the treatment of cancers which may be independent from most tyrosine kinase oncogenes known to be activated in many cancers. Our recent work deals with the elucidation of this novel mechanism. We are using two different approaches:
1. Downregulation of expression of specific cellular genes through the introduction of an anti-message, dominant-negative mutants or siRNA, to demonstrate the overall involvement of a gene product.
2. Introduction of peptides corresponding to the proteins' point(s) of contact using a novel apparatus, to more specifically pinpoint the areas involved.
The reduction in the activity of a signal transducer can demonstrate its overall involvement in the transmission of a signal. To further examine its role, it is imperative to more finely pinpoint the in vivo interactions of different areas of the protein with other members of the cascade. To achieve this, we developed a new technique, termed electroporation in situ. Peptides are introduced corresponding to the proteins' points of contact in order to specifically block their interaction. Recent results demonstrated the exquisite ability of this technique to distinguish between closely related signals and open new avenues for the development of peptidomimetic drugs. This apparatus has been used by over a hundred labs worldwide, with results published in Nature, Science, PNAS and other Journals.
This work has been an excellent training ground for a number of graduate students. Dr Heather Brownell (Ph.D., 1997) was a runner-up for the NSERC doctoral prize and Dr Adina Vultur (Ph.D., 2005) was the recipient of the Governor General's Academic Gold medal as the top graduating Ph.D. student of Queen’s University. Rozanne Arulanandam (Ph.D. candidate), is on her way to being the next. Several more graduate and 4th year project students had external awards and a large number of publications.