Lung cancer is the leading cause of cancer-related mortality, primarily due to metastatic disease. Developing improved metastasis prevention and treatment options will require a better understanding of the specific events involved in tumor progression and metastasis. We have shown that mice expressing mutations commonly found in human lung cancer (KrasG12D and p53R172H) develop metastatic lung adenocarcinomas. Cell lines isolated from tumors in these mice metastasize with high or low frequency following subcutaneous injection into syngeneic mice, dependent upon the expression of the microRNA-200 (miR-200) family members. Since the miR-200 members repress the Zeb family of transcriptional repressors, loss of miR-200 expression results in upregulation of epithelial-to-mesenchymal transition (EMT) genes and metastasis. Coincident with EMT, the metastasis-prone tumor cells lose expression of epithelial polarity complexes, and forced expression of miR-200 restores epithelial polarity and abrogates metastasis. Reciprocally, knockdown of a key component of the basolateral polarity complex, scribble, in a metastasis-incompetent cell suppresses miR-200, increases Zeb-1, and induces metastasis. These findings demonstrate a clear interplay between cell polarity, miR-200, and metastasis. Our global hypothesis is that functional apical-basal polarity complexes are required to maintain miR-200 levels and thereby suppress cancer cell EMT &metastasis. We will test this hypothesis by completing two Aims:
Aim 1 will determine whether invasion and metastasis in scribble-deficient tumors is due entirely to loss of miR-200-mediated suppression of Zeb1;
Aim 2 will determine whether miR-200 suppression and metastasis in the scribble-deficient tumors is due to loss of scribble itself, dysfunction of the larger basolateral complex, which includes the scribble (Scrib), discs large (Dlg1), and lethal giant larvae (Lgl1) proteins, or aberrant interactions of the basolateral complex with the apical polarity complexes, containing the crumbs homolog 3 (Crb3) or partitioning defective 6 (Pard6). A combination of 2D and 3D in vitro models, and syngeneic animal studies will be used to carry out this work, with the aim of understanding how the apical- basal polarity factors regulate cell phenotype through miR-200 fucntion.
Lung cancer is the leading cause of cancer mortality in the U.S., due mainly to the impact of disease metastasis to distant organs. Herein we propose to work with a new combination of in vitro and in vivo models to better understand the process of metastasis. Specifically we plan to study how migratory and invasive characteristics of the tumor are controlled by proteins that determine cellular architecture and cell-cell interaction.
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