During cancer evolution, disseminated cancer cells (DCCs) acquire a variety of molecular traits they use for outgrowth as lethal metastatic colonies in each secondary organ. Among various organ specific “metastatic traits”, DCCs ability to activate YAP (yes associated protein) and MRTF (myocardin related transcription factor) transcriptional programs stands out as a common mechanism necessary for colonization of multiple secondary organs. Therefore, we aim to better understand YAP and MRTF signaling to be able to successfully target widely spread disease.
YAP (and the related TAZ) and MRTFA and B are transcriptional coactivators that relay both biophysical and biochemical information from the microenvironment to cells by regulating gene expression. Biophysical cues that activate YAP and MRTF include extracellular matrix stiffness, membrane tension, pressure and shear stress. All these factors have profound impacts on the reorganization of the actin cytoskeleton, which itself regulates YAP and MRTF. During metastasis, YAP and MRTF activation further potentiates expression of genes involved in actin cytoskeleton remodeling, extracellular matrix production and paracrine signaling which culminates in outgrowth of metastatic colonies. However, spatio-temporal regulation of YAP and MRTF activities within the metastatic microenvironment and the potential DCC vulnerabilities associated with activation of these transcriptional programs remain unknown.
Therefore, we are pursuing several projects related to YAP/MRTF. These are:
· Determining the spatio-temporal, biochemical, biophysical and oncogenic regulation of YAP/MRTF
· Understanding the role YAP/MRTF signaling in the metastatic microenvironment during colonization, immune surveillance, angiogenesis and dormancy
· Dissecting downstream effectors of YAP/MRTF important for metastatic colonization
· Determining the role of YAP/MRTF in epithelial to mesenchymal transition and cellular plasticity
Our approach involves a variety of experimental tools. These vary from traditional histology, molecular and cell biology to generation and use of unique genetic tools for signal perturbation, cellular labeling, clonal isolation, 3-dimensional in vitro, organotropic ex vivo and immunocompetent in vivo models of metastasis. We combine our experimental expertise with bioinformatics and make use of publicly available patient data sets for clinical validation. We always welcome collaborations in biophysical and clinical research.