PUBLICATION

RPTOR blockade suppresses brain metastases of NSCLC by interfering the ceramide metabolism via hijacking YY1 binding

Authors
Lin, Y., Wu, Y., Zhang, Q., Tu, X., Chen, S., Pan, J., Xu, N., Lin, M., She, P., Niu, G., Chen, Y., Li, H.
ID
ZDB-PUB-240103-22
Date
2024
Source
Journal of experimental & clinical cancer research : CR   43: 11 (Journal)
Registered Authors
Keywords
Brain metastasis, Non-small cell lung cancer, RPTOR, S1P, SPHK2
MeSH Terms
  • Zebrafish
  • Carcinoma, Non-Small-Cell Lung*/drug therapy
  • Carcinoma, Non-Small-Cell Lung*/genetics
  • Carcinoma, Non-Small-Cell Lung*/pathology
  • YY1 Transcription Factor/genetics
  • Brain Neoplasms*/drug therapy
  • Brain Neoplasms*/genetics
  • Brain Neoplasms*/pathology
  • Lung Neoplasms*/drug therapy
  • Lung Neoplasms*/genetics
  • Lung Neoplasms*/pathology
  • Ceramides/therapeutic use
  • Regulatory-Associated Protein of mTOR
  • Animals
  • Humans
(all 15)
PubMed
38163890 Full text @ J. Exp. Clin. Cancer Res.
Abstract
Background Ceramide metabolism is crucial in the progress of brain metastasis (BM). However, it remains unexplored whether targeting ceramide metabolism may arrest BM.
Methods RNA sequencing was applied to screen different genes in primary and metastatic foci and whole-exome sequencing (WES) to seek crucial abnormal pathway in BM + and BM-patients. Cellular arrays were applied to analyze the permeability of blood-brain barrier (BBB) and the activation or inhibition of pathway. Database and Co-Immunoprecipitation (Co-IP) assay were adopted to verify the protein-protein interaction. Xenograft and zebrafish model were further employed to verify the cellular results.
Results RNA sequencing and WES reported the involvement of RPTOR and ceramide metabolism in BM progress. RPTOR was significantly upregulated in BM foci and increased the permeability of BBB, while RPTOR deficiency attenuated the cell invasiveness and protected extracellular matrix. Exogenous RPTOR boosted the SPHK2/S1P/STAT3 cascades by binding YY1, in which YY1 bound to the regions of SPHK2 promoter (at -353 ~ -365 nt), further promoting the expression of SPHK2. The latter was rescued by YY1 RNAi. Xenograft and zebrafish model showed that RPTOR blockade suppressed BM of non-small cell lung cancer (NSCLC) and impaired the SPHK2/S1P/STAT3 pathway.
Conclusion RPTOR is a key driver gene in the brain metastasis of lung cancer, which signifies that RPTOR blockade may serve as a promising therapeutic candidate for clinical application.
Genes / Markers
Figures
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Expression
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hkz04tTgTransgenic Insertion
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    Human Disease / Model
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    Sequence Targeting Reagents
    Target Reagent Reagent Type
    rptorCRISPR3-rptorCRISPR
    rptorCRISPR4-rptorCRISPR
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    Fish
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    Antibodies
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    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
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    Mapping
    No data available
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    Citation
    Lin, Y., Wu, Y., Zhang, Q., Tu, X., Chen, S., Pan, J., Xu, N., Lin, M., She, P., Niu, G., Chen, Y., Li, H. (2024) RPTOR blockade suppresses brain metastases of NSCLC by interfering the ceramide metabolism via hijacking YY1 binding. Journal of experimental & clinical cancer research : CR. 43:11.