Control of lung cancer invasion and metastasis by vimentin

Summary

Principal Investigator: Adam I Marcus
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2011-03-01 - 2016-02-29
more information: NIH RePORT

Top Publications

  1. pmc STE20-related kinase adaptor protein α (STRADα) regulates cell polarity and invasion through PAK1 signaling in LKB1-null cells
    Carrie M Eggers
    Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA
    J Biol Chem 287:18758-68. 2012
  2. pmc AMPK regulates mitotic spindle orientation through phosphorylation of myosin regulatory light chain
    Jose T Thaiparambil
    Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
    Mol Cell Biol 32:3203-17. 2012
  3. pmc LKB1 represses focal adhesion kinase (FAK) signaling via a FAK-LKB1 complex to regulate FAK site maturation and directional persistence
    Erik R Kline
    Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    J Biol Chem 288:17663-74. 2013
  4. pmc Energizing the search to target LKB1-mutant tumors
    Adam I Marcus
    Department of Hematology and Medical Oncology and the Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
    Cancer Discov 3:843-5. 2013
  5. pmc Automated quantification of the subcellular localization of multicompartment proteins via Q-SCAn
    Nicholas C Bauer
    Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
    Traffic 14:1200-8. 2013

Research Grants

Detail Information

Publications7

  1. pmc STE20-related kinase adaptor protein α (STRADα) regulates cell polarity and invasion through PAK1 signaling in LKB1-null cells
    Carrie M Eggers
    Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA
    J Biol Chem 287:18758-68. 2012
    ..It also suggests that while the function of LKB1 and STRADα undoubtedly overlap, they may also have mutually exclusive roles...
  2. pmc AMPK regulates mitotic spindle orientation through phosphorylation of myosin regulatory light chain
    Jose T Thaiparambil
    Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
    Mol Cell Biol 32:3203-17. 2012
    ..Taken together, these data indicate that AMPK mediates spindle pole-associated pMRLC(ser19) to control spindle orientation via regulation of actin cortex-astral microtubule attachments...
  3. pmc LKB1 represses focal adhesion kinase (FAK) signaling via a FAK-LKB1 complex to regulate FAK site maturation and directional persistence
    Erik R Kline
    Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    J Biol Chem 288:17663-74. 2013
    ....
  4. pmc Energizing the search to target LKB1-mutant tumors
    Adam I Marcus
    Department of Hematology and Medical Oncology and the Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
    Cancer Discov 3:843-5. 2013
    ..The work presented here by Liu and colleagues shows that deoxythymidylate kinase is a new potential target in LKB1-deficient tumors and highlights the possibility of a new therapeutic option for this subset of patients with cancer...
  5. pmc Automated quantification of the subcellular localization of multicompartment proteins via Q-SCAn
    Nicholas C Bauer
    Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
    Traffic 14:1200-8. 2013
    ..Our findings demonstrate the utility of Q-SCAn for quantitative analysis of the subcellular distribution of multicompartment proteins. ..

Research Grants30

  1. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..