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Emily B Harrison



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    P65 - Tumor Biology and Systems Biology - Basic and Translational Science - NC RNA (ID 204)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P65.03 - A Circle RNA Regulatory Axis Promotes Lung Squamous Metastasis via CDR1 Regulation of Golgi Trafficking (ID 3083)

      00:00 - 00:00  |  Presenting Author(s): Emily B Harrison

      • Abstract
      • Slides

      Introduction

      Lung squamous carcinoma (LUSC) is a highly metastatic disease with a poor prognosis and no actionable oncogenes. Non-coding RNAs are key regulators of metastatic programs, but their role in LUSC remains elusive.

      Methods

      Using an integrated systems biology approach, we selected microRNAs (miRs) with survival relevance for LUSC patients (n=348) and differential expression in two novel, highly metastatic LUSC models. Following validation of our screen, the importance of a non-coding RNA axis and downstream targets were evaluated using gain- and loss-of-function in vivo assessments and molecular profiling of a well-annotated tissue microarray. To elucidate downstream mechanisms, we identified direct protein interactors and performed confocal microscopy, epistasis migration assays, and state-of-the-art ER-Golgi trafficking experiments.

      Results

      We found that miR-671-5p was associated with survival (HR=0.56, 95% CI 0.39 to 0.80, p=0.002) and suppressed in metastatic sub-clones. Functionally, miR-671-5p reduced LUSC metastasis by silencing a circular RNA (circRNA), CDR1as, and its anti-sense transcript, cerebellar degeneration related protein 1 (CDR1). CDR1as and CDR1 were increased in LUSC tumors relative to normal lungs, and CDR1 was strongly associated with epithelial-to-mesenchymal transition (EMT) signatures. Silencing of CDR1as or CDR1 in animal models inhibited metastases, and CDR1 was sufficient to promote migration, metastases, and ER-Golgi trafficking. CDR1, which directly interacted with adaptor protein 1 (AP1) complex subunits and COPI proteins, no longer promoted migration upon blockade of Golgi trafficking.

      Conclusion

      Our findings reveal a miR/circRNA axis that regulates LUSC metastases through a previously unstudied protein, CDR1. CDR1, discovered as an onconeural antigen, is strongly linked with EMT and enhances ER-Golgi trafficking and metastases in LUSC.

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