Northwestern University Feinberg School of Medicine

Karen Ridge Lab

Vimentin and Metastasis in Non–Small Cell Lung Cancer

Lung cancer is the leading cause of cancer deaths in the United States [1]. Non–small cell lung cancer (NSCLC) represents 80% of all lung cancers [2]. At the time of NSCLC diagnosis, 40–50% of patients already have stage 4 disease and a 5-year survival rate of <1%. Up to one-half of the remaining patients who undergo curative surgery will have recurrence with metastatic disease [1,3]. At present, there are no treatments that target the process of metastatic spread. Vimentin, a type 3 intermediate filament, is involved in multiple steps of the metastatic cascade, including epithelial-to mesenchymal transition (EMT), breach of the basement membrane, dissociation of cells from the original tumor, invasion into new tissue, and establishment at a secondary site [2]. Vimentin expression is upregulated in NSCLC and is used as a diagnostic marker to distinguish between the initial progression of localized epithelial cells and the invasive spread of metastatic tumor cells [4,5].

Multiple gene abnormalities contribute to the development of NSCLC. Two of the most common mutations are to the oncogene Kras and to the tumor suppressor gene p53 [6]. To investigate the role of vimentin in the development and progression of NSCLC, we use a mouse model in which lung adenocarcinomas are induced by Cre recombinase–mediated expression of a mutant Kras allele. We crossed these LSL-KrasG12D/+ mice with mice harboring floxed alleles of Tp53 to create a model of metastatic lung cancer. We then crossed the resultant mice with vimentin-null mice. Compared with wild-type mice with induced lung adenocarcinoma, the vimentin-null mice had prolonged survival, decreased tumor burden, and decreased lymph node involvement, suggesting a reduction in the spread of metastatic cancer cells. The compound withaferin A is a steroidal lactone that binds to vimentin and causes disassembly of the network. Withaferin A has been shown to inhibit cancer cell migration in vitro [7]. When wild-type mice with induced lung adenocarcinoma were treated with withaferin A, they showed evidence of slower tumor progression than did untreated mice. These findings shine a hopeful light on the treatment of NSCLC in the future.

References: (1) Hammerschmidt S, & Wirtz H. Lung cancer: current diagnosis and treatment. Dtsch Arztebl Int. 2009 Dec;106(49):809-18. (2) Kidd ME, et al. The role of vimentin intermediate filaments in the progression of lung cancer. Am J Respir Cell Mol Biol. 2014 Jan;50(1):1-6. (3) Kahn N, et al. Early detection of lung cancer by molecular markers in endobronchial epithelial-lining fluid. J Thorac Oncol. 2012 Jun;7(6):1001-8. (4) Rogel MR, et al. Vimentin is sufficient and required for wound repair and remodeling in alveolar epithelial cells. FASEB J. 2011 Nov;25(11):3873-83. (5) Helfand BT, et al. Vimentin organization modulates the formation of lamellipodia. Mol Biol Cell. 2011 Apr 15;22(8):1274-89. (6) Herbst RS, et al. Lung cancer. N Engl J Med. 2008 Sep 25;359(13):1367-80. (7) Ridge KM, et al. Methods for determining the cellular functions of vimentin intermediate filaments. Methods Enzymol. 2016;568:389-426.