Lung cancer is the most lethal malignant cancer worldwide and results in over 150,000 deaths per year in the United States. In particular, non-small cell lung cancer (NSCLC), which accounts for nearly 80% of all lung cancers, has a 5-year survival rate ranging from only 15-25%. Numerous reports show that the intermediate filament protein vimentin is overexpressed in invasive human tumors but is nearly undetectable in non- invasive, stationary tumors. In NSCLC, vimentin expression correlates with poor survival, increased metastatic disease, and poor differentiation. Nevertheless, the mechanistic role of vimentin in NSCLC is unexplored. Here we show that the STRAD1-LKB1 lung cancer tumor suppressor pathway, which is mutated in 30% of NSCLC patients and is the 3rd highest mutated pathway in NSCLC, regulates vimentin function during lung cancer motility. Thus, we link vimentin to a robust NSCLC tumor suppressor pathway. We will test the central hypothesis that during lung cancer invasion, vimentin is overseen by STRAD1-LKB1 and participates in a positive feedback loop that maintains directionality persistence. Our objectives are to determine how STRAD1-LKB1 oversees vimentin function, how vimentin goes on to regulate NSCLC motility, and the molecular and clinical consequences of vimentin expression in NSCLC patients. Importantly, we have published that STRAD1-LKB1 interact with the canonical cell polarity and motility proteins cdc42-PAK1. We build upon this data to determine whether STRAD1-LKB1 regulate vimentin through cdc42-PAK1. Moreover, we propose that vimentin then goes on to regulate NSCLC directionality persistence through a positive feedback loop containing cdc42, and the cdc42 guanine exchange factor (GEF) VAV2. We take an innovative and comprehensive mechanistic approach by combining state-of-the-art cell and molecular biology, in vivo xenograft models, and patient tissue-based approaches to fully translate these findings. By understanding how STRAD1-LKB1 regulates vimentin and how vimentin expression contributes to NSCLC metastasis, we can impact our understanding of the biology of LKB1 mutant (~50,000 patients) and vimentin overexpressing NSCLC patients. Thus, this proposal can develop a new paradigm for vimentin function in NSCLC and present vimentin as a major player in the regulation of lung cancer metastatic invasion.

Public Health Relevance

Vimentin expression correlates with metastatic disease, poor prognosis, and reduced patient survival in lung cancer. Nevertheless, the mechanistic role of vimentin in lung cancer metastasis has been unexplored. This proposal takes a comprehensive translational approach to understand how vimentin oversees lung cancer metastasis using in vitro, in vivo, and lung cancer patient tissue studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA142858-03
Application #
8444554
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2013
Total Cost
$302,328
Indirect Cost
$107,278
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Liu, Fakeng; Jin, Rui; Liu, Xiuju et al. (2016) LKB1 promotes cell survival by modulating TIF-IA-mediated pre-ribosomal RNA synthesis under uridine downregulated conditions. Oncotarget 7:2519-31
Gilbert-Ross, Melissa; Marcus, Adam I; Zhou, Wei (2015) RhoA, a novel tumor suppressor or oncogene as a therapeutic target? Genes Dis 2:2-3
Mattheyses, Alexa L; Marcus, Adam I (2015) Förster resonance energy transfer (FRET) microscopy for monitoring biomolecular interactions. Methods Mol Biol 1278:329-39
Havel, L S; Kline, E R; Salgueiro, A M et al. (2015) Vimentin regulates lung cancer cell adhesion through a VAV2-Rac1 pathway to control focal adhesion kinase activity. Oncogene 34:1979-90
Zhou, Wei; Zhang, Jun; Marcus, Adam I (2014) LKB1 Tumor Suppressor: Therapeutic Opportunities Knock when LKB1 Is Inactivated. Genes Dis 1:64-74
Marcus, Adam I; Khuri, Fadlo R (2013) Energizing the search to target LKB1-mutant tumors. Cancer Discov 3:843-5
Kline, Erik R; Shupe, John; Gilbert-Ross, Melissa et al. (2013) LKB1 represses focal adhesion kinase (FAK) signaling via a FAK-LKB1 complex to regulate FAK site maturation and directional persistence. J Biol Chem 288:17663-74
Thaiparambil, Jose T; Eggers, Carrie M; Marcus, Adam I (2012) AMPK regulates mitotic spindle orientation through phosphorylation of myosin regulatory light chain. Mol Cell Biol 32:3203-17
Eggers, Carrie M; Kline, Erik R; Zhong, Diansheng et al. (2012) STE20-related kinase adaptor protein α (STRADα) regulates cell polarity and invasion through PAK1 signaling in LKB1-null cells. J Biol Chem 287:18758-68