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bioRxiv · 10.1101/2020.06.04.130963

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

Berr, A. L.·Wiese, K.·dos Santos, G.·Davis, J.·Koch, C.·Anekalla, K. R.·Kidd, M.·Cheng, Y.·Hu, Y.-S.·Ridge, K.
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Abstract

Vimentin, a type III intermediate filament, is highly expressed in aggressive epithelial cancers and is associated with increased rates of metastasis. We show that vimentin is causally required for lung cancer metastasis using a genetic mouse model of lung adenocarcinoma (LSL-KrasG12D;Tp53fl/fl, termed KPV+/+) crossed with vimentin-null mice (thereby creating KPV-/- mice). Both KPV+/+ and KPV-/- mice developed lung tumors, yet KPV-/- mice had delayed tumorigenesis and prolonged survival. KPV+/+ cells implanted in the flank metastasized to the lung while KPV-/- cells did not, providing additional evidence that vimentin is required for metastasis. Differential expression analysis of RNA-seq data demonstrated that KPV-/- cells had suppressed expression of genes that drive epithelial-to-mesenchymal transition, migration, and invasion, processes that are critical to the metastatic cascade. Integrative metabolomic and transcriptomic analysis revealed altered glutaminolysis, with KPV-/- cells accumulating glutathione, leading to impaired cell motility in response to oxidative stress. Together, these results show that loss of vimentin impairs epithelial-to-mesenchymal transition and regulation of the oxidative stress response, resulting in decreased metastasis in murine lung adenocarcinoma.

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Berr, A. L., Wiese, K., dos Santos, G., Davis, J., Koch, C., Anekalla, K. R., Kidd, M., Cheng, Y., Hu, Y.-S., Ridge, K.. 2020-06-05. Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer. https://doi.org/10.1101/2020.06.04.130963

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