The 3rd most commonly mutated gene in lung adenocarcinoma is the kinase LKB1 (STK11), where ~25,000 patients have this mutation. Patients that are co-mutated for LKB1 and KRAS have significantly shorter overall survival compared to either mutation alone and have no effective targeted therapies. In a genetically engineered Kras mouse model, co-mutation of Lkb1 is sufficient to promote metastasis of lung adenocarcinoma, and primary tumors and metastases show aberrant activation of both EMT and adhesion signaling. In agreement with these data, we have published three reports that LKB1 regulates lung cancer motility and when present, restrict the activity of a key adhesion signaling molecule, focal adhesion kinase (FAK). Moreover, our preliminary data show that Lkb1-deficient tumor cells invade as a collective pack in vivo, and in doing so, remodel the collagen ECM of the tumor microenvironment, a phenomenon that is dependent on the activity of FAK in vitro. These metastatic tumors from the mouse model show aberrant FAK activation within collective invasion packs of the primary tumors. Therefore, we hypothesize that LKB1-mutant cells use EMT to initially invade through the basement membrane, which is followed by defective FAK-based adhesion signaling that allows cells to navigate the collagen microenvironment during metastasis. To test this, we will take a multi-model approach that combines the power of Drosophila and mouse genetics, and our large clinically annotated human lung adenocarcinoma tumor bank to i) test the mechanism and signaling pathway used by Lkb1-mutant cells to traverse the basement membrane, ii) determine whether altered adhesion signaling drives in vivo cell escape through collagen remodeling, and iii) determine whether LKB1-mutant human lung adenocarcinoma exhibits altered adhesion signaling that correlates with collagen remodeling and predicts poor outcome. We propose that this comprehensive approach can overcome the shortcomings of traditional in vitro systems and address our goal of defining the biological consequences of LKB1 mutations in lung cancer patients.

Public Health Relevance

LKB1 is mutated in 20-30% of non-small cell lung cancers and ranks as the 3rd most frequently mutated gene in lung adenocarcinoma. LKB1 loss drives cancer metastasis; therefore, we will dissect LKB1 function in vitro and in vivo to understand the link between LKB1 loss and cancer metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA201340-02
Application #
9196337
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2015-12-16
Project End
2020-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
2
Fiscal Year
2017
Total Cost
$332,838
Indirect Cost
$116,361
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Richardson, Alessandra M; Havel, Lauren S; Koyen, Allyson E et al. (2018) Vimentin Is Required for Lung Adenocarcinoma Metastasis via Heterotypic Tumor Cell-Cancer-Associated Fibroblast Interactions during Collective Invasion. Clin Cancer Res 24:420-432
Wilkinson, S; Hou, Y; Zoine, J T et al. (2017) Coordinated cell motility is regulated by a combination of LKB1 farnesylation and kinase activity. Sci Rep 7:40929
Gilbert-Ross, Melissa; Konen, Jessica; Koo, Junghui et al. (2017) Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma. JCI Insight 2:e90487
Lee, Byoungkoo; Konen, Jessica; Wilkinson, Scott et al. (2017) Local alignment vectors reveal cancer cell-induced ECM fiber remodeling dynamics. Sci Rep 7:39498
Konen, Jessica; Wilkinson, Scott; Lee, Byoungkoo et al. (2016) LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion. Mol Biol Cell 27:1069-84