Vimentin is required for tumor progression and metastasis in a mouse model of non–small cell lung cancer

Vimentin is highly expressed in metastatic cancers, and its expression correlates with poor patient prognoses. However, no causal in vivo studies linking vimentin and non–small cell lung cancer (NSCLC) progression existed until now. We use three complementary in vivo models to show that vimentin is required for the progression of NSCLC. First, we crossed LSL-Kras(G12D); Tp53(fl/fl) mice (KPV(+/+)) with vimentin knockout mice (KPV(−/−)) to demonstrate that KPV(−/−) mice have attenuated tumor growth and improved survival compared with KPV(+/+) mice. Next, we therapeutically treated KPV(+/+) mice with withaferin A (WFA), an agent that disrupts vimentin intermediate filaments (IFs). We show that WFA suppresses tumor growth and reduces tumor burden in the lung. Finally, luciferase-expressing KPV(+/+), KPV(−/−), or KPV(Y117L) cells were implanted into the flanks of athymic mice to track cancer metastasis to the lung. In KPV(Y117L) cells, vimentin forms oligomers called unit-length filaments but cannot assemble into mature vimentin IFs. KPV(–/–) and KPV(Y117L) cells fail to metastasize, suggesting that cell-autonomous metastasis requires mature vimentin IFs. Integrative metabolomic and transcriptomic analysis reveals that KPV(–/–) cells upregulate genes associated with ferroptosis, an iron-dependent form of regulated cell death. KPV(–/–) cells have reduced glutathione peroxidase 4 (GPX4) levels, resulting in the accumulation of toxic lipid peroxides and increased ferroptosis. Together, our results demonstrate that vimentin is required for rapid tumor growth, metastasis, and protection from ferroptosis in NSCLC.