Northwestern University Feinberg School of Medicine

Karen Ridge Lab

Vimentin and Metastasis in Non–Small Cell Lung Cancer

Role of vimentin in the metastatic cascade. Click for larger image.

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.

Role of vimentin in the metastatic cascade. Click for larger image.