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RBFOX2 deregulation promotes pancreatic cancer progression and metastasis through alternative splicing

Author

Listed:
  • Michelle Maurin

    (Moffitt Cancer Center)

  • Mohammadreza Ranjouri

    (Moffitt Cancer Center)

  • Cristina Megino-Luque

    (Icahn School of Medicine at Mount Sinai)

  • Justin Y. Newberg

    (Moffitt Cancer Center)

  • Dongliang Du

    (Moffitt Cancer Center)

  • Katelyn Martin

    (Moffitt Cancer Center)

  • Robert E. Miner

    (Moffitt Cancer Center)

  • Mollie S. Prater

    (St. Jude Children’s Research Hospital)

  • Dave Keng Boon Wee

    (Technology and Research (A*STAR))

  • Barbara Centeno

    (Moffitt Cancer Center)

  • Shondra M. Pruett-Miller

    (St. Jude Children’s Research Hospital)

  • Paul Stewart

    (Moffitt Cancer Center)

  • Jason B. Fleming

    (Moffitt Cancer Center)

  • Xiaoqing Yu

    (Moffitt Cancer Center)

  • Jose Javier Bravo-Cordero

    (Icahn School of Medicine at Mount Sinai)

  • Ernesto Guccione

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Michael A. Black

    (University of Otago)

  • Karen M. Mann

    (Moffitt Cancer Center
    Moffitt Cancer Center)

Abstract

RNA splicing is an important biological process associated with cancer initiation and progression. However, the contribution of alternative splicing to pancreatic cancer (PDAC) development is not well understood. Here, we identify an enrichment of RNA binding proteins (RBPs) involved in splicing regulation linked to PDAC progression from a forward genetic screen using Sleeping Beauty insertional mutagenesis in a mouse model of pancreatic cancer. We demonstrate downregulation of RBFOX2, an RBP of the FOX family, promotes pancreatic cancer progression and liver metastasis. Specifically, we show RBFOX2 regulates exon splicing events in transcripts encoding proteins involved in cytoskeletal remodeling programs. These exons are differentially spliced in PDAC patients, with enhanced exon skipping in the classical subtype for several RBFOX2 targets. RBFOX2 mediated splicing of ABI1, encoding the Abelson-interactor 1 adapter protein, controls the abundance and localization of ABI1 protein isoforms in pancreatic cancer cells and promotes the relocalization of ABI1 from the cytoplasm to the periphery of migrating cells. Using splice-switching antisense oligonucleotides (AONs) we demonstrate the ABI1 ∆Ex9 isoform enhances cell migration. Together, our data identify a role for RBFOX2 in promoting PDAC progression through alternative splicing regulation.

Suggested Citation

  • Michelle Maurin & Mohammadreza Ranjouri & Cristina Megino-Luque & Justin Y. Newberg & Dongliang Du & Katelyn Martin & Robert E. Miner & Mollie S. Prater & Dave Keng Boon Wee & Barbara Centeno & Shondr, 2023. "RBFOX2 deregulation promotes pancreatic cancer progression and metastasis through alternative splicing," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44126-w
    DOI: 10.1038/s41467-023-44126-w
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    References listed on IDEAS

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