The most frequent cause of death in patients with non-small cell lung cancer (NSCLC) is metastasis. Currently, there are no effective means to prevent metastasis in NSCLC patients. Oncogenic somatic mutations in K-ras, which encodes a membrane-associated GTPase, occur in approximately 30% of lung adenocarcinomas, the most common subtype of NSCLC. Mice that express oncogenic K-ras develop lung adenocarcinomas with high penetrance, but the long latency periods and low metastatic potential of these tumors imply that K-ras mutations are only sufficient to initiate the development of lung adenocarcinomas and that other genetic events are required for the lung tumors to metastasize. One gene that may be involved in lung adenocarcinoma metastasis is MAP2K4, which encodes the stress- and cytokine-regulated mitogen activated protein kinase kinase-4 (MKK4). Eleven different MKK4 somatic mutations that cluster within the MKK4 kinase domain have been identified in human tumor specimens. We have generated these mutants and found that the majority (8 of 11) have loss-of-function. On the basis of previous reports that MKK4 acts as a metastasis suppressor in cancer cells, we postulate that MKK4 loss-of-function mutations confer metastatic potential to K-ras- mutant lung adenocarcinoma cells. We will test this hypothesis by creating a mouse model that conditionally inactivates MKK4 and expresses oncogenic K-ras in the lung (Aim 1). We will derive metastatic lung adenocarcinoma cell lines from these mice and use them in a syngeneic tumor model to determine whether MKK4 inactivation is required for lung adenocarinoma cells to acquire metastasis "skills" including the ability to undergo epithelial-to-mesenchymal transition (EMT), which is a phenotypic change characterized by a loss of cellular polarity, a breakdown of cell-cell adhesions, and enhanced invasive properties (Aim 2);to recruit myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), which promote metastasis by suppressing anti-tumor immunity and promoting tumor cell invasion through a metalloproteinase-dependent mechanism (Aim 3);and to colonize and proliferate at distant sites (Aim 4). If our findings support this hypothesis, then clinical studies would be warranted to examine whether the presence of mutations in K-ras and MKK4 together identify a subset of patients who are at high risk for metastasis and would benefit from additional therapy to prevent disease recurrence.
Lung cancer is the most common cause of cancer-related death in the United States, and metastasis is the most common cause of death in lung cancer patients. New approaches are needed for the prevention of metastasis in patients with lung cancer. Studies have shown that K-ras mutations are common in human lung adenocarcinomas and are sufficient to initiate the development of lung adenocarcinomas in mice, but other genetic events are required for the subsequent metastasis of these tumors. In this project, we will test the hypothesis that inactivating mutations in MKK4, a gene that is frequently mutated in a variety of human cancer types including lung cancer, promote the metastasis of K-ras-mutant lung cancer cells. We will examine whether MKK4 inactivation causes these cells to develop the skills to metastasize, including the ability to recruit inflammatory cells that promote cancer cell invasion and dissemination. If our findings support this hypothesis, then clinical studies would be warranted to examine whether the presence of mutations in K-ras and MKK4 together identify a subset of patients who are at high risk for metastasis and would benefit from additional therapy to prevent disease recurrence.
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