Lung cancer is the leading cause of cancer related deaths in the United States largely due to patients being diagnosed at late stages when metastasis has already occurred. A major mechanism of cancer metastasis is a process known as the epithelial-to-mesenchymal transition (EMT). During EMT, epithelial cells of the primary tumor undergo genetic and epigenetic alterations that allow them to change their morphology from a polarized and anchored cell to an invasive mesenchymal cell. EMT markers include the loss of E-cadherin and gain of N-cadherin, fibronectin, and vimentin expression. Vimentin is a classical EMT marker that historically correlates with metastasis and poor overall survival across multiple tumor types; however, little is known about the mechanisms by which vimentin expression triggers cell motility and invasion. Our lab has demonstrated that vimentin regulates focal adhesion kinase (FAK) to stabilize focal adhesions essential for motility. This is important since it provides a functional role for vimentin to control cell motility and adhesion. Moreover, previous work shows that vimentin morphology and dynamics are mediated by serine phosphorylation in its head domain. Therefore, we will test the central hypothesis that serine phosphorylation events mediate vimentin dynamics to control focal adhesion activity and, therefore, cancer cell invasion and metastasis. To test this, we will determine 1) the mechanism by which serine phosphorylation in the vimentin head domain mediates its dynamics and function in cell adhesion and 2) the in vivo metastatic phenotypes driven by these vimentin phosphorylation events. This approach will allow us to combine in vitro experiments using innovative 3-D multicellular lung spheroid models along with in vivo xenografts. Furthermore, we will incorporate cutting- edge multi-photon imaging of lung explants to visualize the impact of vimentin expression on real-time metastasis. Our overarching goal is to use this information to decipher vimentin function in invasive lung cancer and thereby probe the molecular basis of lung cancer EMT.
Lung cancer is the leading cause of cancer related deaths in the United States due to patients being diagnosed at a late stage when metastasis has already occurred. In order to prevent metastasis and improve patient outcomes, it is important to understand the mechanisms driving metastasis. We propose to study a major mechanism of metastasis, the vimentin cytoskeleton, to further improve our understanding of lung cancer biology.
|Richardson, Alessandra M; Havel, Lauren S; Koyen, Allyson E et al. (2018) Vimentin Is Required for Lung Adenocarcinoma Metastasis via Heterotypic Tumor Cell-Cancer-Associated Fibroblast Interactions during Collective Invasion. Clin Cancer Res 24:420-432|