Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Berr AL

PROVIDER: S-EPMC10275760 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Berr Alexandra L AL Wiese Kristin K Dos Santos Gimena G Koch Clarissa M CM Anekalla Kishore R KR Kidd Martha M Davis Jennifer M JM Cheng Yuan Y Hu Yuan-Shih YS Ridge Karen M KM

Oncogene 20230509 25

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-KrasG12D; Tp53fl/fl mice (KPV+/+) with vimentin knockout mice (KPV-/-) to demonstrate that KPV< ...[more]

PMID: 37161053

Similar Datasets

Project description:IntroductionLung cancer remains the leading cause of tumor-related deaths, despite advances in the understanding of the disease pathogenesis and in its clinical treatment. It is crucial to develop novel technologies to discover disease biomarkers and predict individual therapy response.Materials and methodsWe established 48 patients-derived tumor xenografts (PDTXs) implanted in the subrenal capsule of immunodeficient mice using thin, precision-cut tumor tissue slices, derived from five patients affected by non-small cell lung cancer. Twenty-six tissue slices were immediately processed and implanted at sample recovery [patients-derived tumor xenografts derived from fresh tissue (dPDTX)], whereas the remaining sections were cultured on specific organotypic supports at 37°C and 5% CO2 for 24 h before grafting [patients-derived tumor xenografts derived from cultured tissue (cPDTX)]. At sacrifice, xenografts tissue morphology, proliferation (Ki67), and histotype markers were analyzed. Oncogenic miRNAs profiles were assessed in PDTXs, human tumors, and serum from one patient.ResultsXenografts retained the original cancer features and there were no differences between dPDTXs and cPDTXs. Squamous cell carcinoma (SCC) xenografts showed a higher engraftment rate than adenocarcinoma (AC)-derived tumors. At basal time, Ki67 levels were higher in SCCs than in ACs, and the expression levels of genes associated to a stem cell-like phenotype were also more expressed in SCC samples. The analysis of oncogenic miRNAs showed that circulating miR-19b, -21, and -210 levels were correlated with higher Ki67 expression in xenografts.ConclusionOur study implemented the PDTX model with thin, precision-cut tumor slices from small tumors, which could be useful for clinical applications and predictive purposes. The different engraftment success is likely determined by tumor histotype, high proliferation index, and the expression of genes essential for cancer stem cells maintenance. Our PDTXs model could be a valid tool to expand primary tumors for the discovery of new biomarkers and explore therapeutic options.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets