Mammary Gland Development in Breast Cancer
Parallels between embryogenesis and cancer have been recognized for well over a century. However, the molecular basis for these similarities has remained obscure. Our group has been working to unravel the specific molecular regulatory networks that govern early tissue development and stem cell control in order to identify pathways co-opted in the development, perpetuation and progression of cancer. Understanding these networks promises new avenues for individualized molecular therapies, including the ability to target potentially rare cells within heterogeneous tumor that may act as essential stem cells for the tumor tissue.
Pancreatic ductal adenocarninoma (PDA) is one of the most aggressive human cancers with a median survival of 6 months after diagnosis. Most patients present with locally advanced or metastatic disease and the current standard of care produces only modest survival benefit.
The lab has long had the perspective that the types of experiments we can do are limited by the methods available. The first innovation was a method to improve nucleic acid hybridization and detection, followed by the development of the Flp recombinase system for use in mammalian cells. Powerful methods for studying chromosome dynamics in real time benefitted from the lab’s development of a fluorescently labeled histone, H2B-GFP, now used in hundreds of labs worldwide.
Most recently, the lab developed ReBiL, a powerful technique to study protein-protein interactions in real time in living cells as described in more detail below. Now, the lab is working to develop new methods for bioinformatic analysis of large transcriptomic and epigenetic data sets, methods to indelibly label and track cell-cell interactions, and better mouse models to study breast, pancreas and other cancers.
The human protein “interactome” may involve ~130,000 to ~650,000 protein-protein interactions (PPIs). The mutations that lead to cancer often perturb PPIs and as a consequence change signal transduction pathways that regulate cell growth, death, control of genetic stability, interaction between cells, etc . Currently, a critical unmet need is the availability of real time assays that directly measure PPIs in living cells. Such an assay would enable the consequences of cancer associated mutations to perturb specific PPIs, and to evaluate their consequences on diverse biologic processes relevant to cancer and other diseases.