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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA105155-09
Application #
8254442
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Salnikow, Konstantin
Project Start
2004-02-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$243,904
Indirect Cost
$85,525
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Ahn, Young-Ho; Yang, Yanan; Gibbons, Don L et al. (2011) Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing peroxisome proliferator-activated receptor ?2 expression. Mol Cell Biol 31:4270-85
Ahn, Young-Ho; Kurie, Jonathan M (2009) MKK4/SEK1 is negatively regulated through a feedback loop involving the E3 ubiquitin ligase itch. J Biol Chem 284:29399-404
Yang, Yanan; Iwanaga, Kentaro; Raso, Maria Gabriela et al. (2008) Phosphatidylinositol 3-kinase mediates bronchioalveolar stem cell expansion in mouse models of oncogenic K-ras-induced lung cancer. PLoS One 3:e2220
Iwanaga, Kentaro; Yang, Yanan; Raso, Maria Gabriela et al. (2008) Pten inactivation accelerates oncogenic K-ras-initiated tumorigenesis in a mouse model of lung cancer. Cancer Res 68:1119-27
Khatlani, T S; Wislez, M; Sun, M et al. (2007) c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells. Oncogene 26:2658-66
Wislez, Marie; Fujimoto, Nobukazu; Izzo, Julie G et al. (2006) High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic kras. Cancer Res 66:4198-207
Wislez, Marie; Spencer, M Loreto; Izzo, Julie G et al. (2005) Inhibition of mammalian target of rapamycin reverses alveolar epithelial neoplasia induced by oncogenic K-ras. Cancer Res 65:3226-35
Fujimoto, Nobukazu; Wislez, Marie; Zhang, Jie et al. (2005) High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res 65:11478-85
Amann, Joseph; Kalyankrishna, Shailaja; Massion, Pierre P et al. (2005) Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res 65:226-35