Our goal is to better understand the biologic basis for metastasis of KRAS-mutant lung adenocarcinoma and to develop novel therapeutic approaches on the basis of that improved understanding. Progress in this area could potentially have a tremendous public health impact because metastasis is the primary cause of death from lung cancer, and there are currently few effective therapeutic options for KRAS-mutant lung adenocarcinoma. Here, we show that the Zeb1, a transcriptional driver of epithelial-to-mesenchymal transition (EMT) and bonafide driver of malignant progression and predictor of poor clinical outcome in multiple epithelial tumor types, induces an amoeboid migratory switch through the downregulation of microRNAs (miR-34a and miR-148a). Thus, we postulate that Zeb1 promotes metastasis of K-ras-mutant lung adenocarcinoma by inducing an amoeboid switch through the downregulation of miR-34a and miR-148a. To test this hypothesis, we propose two Specific Aims.
The first Aim i s to determine whether mediators of Zeb1 that promote an amoeboid switch are required for lung adenocarcinoma metastasis. The studies in Aim 1 will incorporate a new tool for in vivo microscopic imaging of migratory tumor cells in the lung and will be validated using specimens from a large, well-annotated human lung cancer tissue bank.
The second Aim i s to determine whether inactivation of Mir34 gene loci (Mir34a, Mir34bc, or both), which are frequently silenced in human lung cancer, induces metastasis in mice that develop lung adenocarcinoma from expression of mutant K-ras. If our hypothesis is correct, these findings will advance our understanding of the mechanisms by which Zeb1 promotes metastasis, will provide researchers in the field with new tools to investigate the migratory dynamics of tumor cells in the lung and the underlying causes of lung adenocarcinoma metastasis, and will provide a basis for investigating agents that target mediators of Zeb1 in clinical trials. Such trials are already underway;miR-34a liposomal particles are currently being tested in a phase I clinical trial in patients with advanced cancer.
There are few effective therapeutic options for patients with metastatic KRAS-mutant lung adenocarcinoma, and there is an urgent need to develop a better understanding of the biological basis of metastasis that will lead to the identification of rationa therapeutic targets for patients with KRAS-mutant lung adenocarcinoma. On the basis of the preliminary results presented here, we postulate that the ZEB1 transcriptional repressor, which is a bonafide driver of solid tumor metastasis, promotes the metastasis of KRAS-mutant lung adenocarcinoma by inducing an amoeboid migratory switch driven through the downregulation of tumor suppressive microRNAs (miR-34a and miR-148a). If proven true, these findings would advance our understanding of the mechanisms by which Zeb1 promotes metastasis and would warrant clinical studies to determine whether miR-34a mimics, which are currently in clinical trials, prevent metastasis and do so most effectively in lung adenocarcinomas with KRAS mutations.