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Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage

Author

Listed:
  • Pietro Carotenuto

    (The Institute of Cancer Research
    TIGEM – Telethon Institute of Genetics and Medicine)

  • Francesco Amato

    (University of Glasgow)

  • Andrea Lampis

    (The Institute of Cancer Research)

  • Colin Rae

    (University of Glasgow)

  • Somaieh Hedayat

    (The Institute of Cancer Research)

  • Maria C. Previdi

    (The Institute of Cancer Research)

  • Domenico Zito

    (The Institute of Cancer Research)

  • Maya Raj

    (The Institute of Cancer Research)

  • Vincenza Guzzardo

    (University of Padua)

  • Francesco Sclafani

    (The Royal Marsden NHS Trust, London and Surrey)

  • Andrea Lanese

    (The Royal Marsden NHS Trust, London and Surrey)

  • Claudia Parisi

    (The Royal Marsden NHS Trust, London and Surrey)

  • Caterina Vicentini

    (, University of Verona)

  • Ian Said-Huntingford

    (The Institute of Cancer Research)

  • Jens C. Hahne

    (The Institute of Cancer Research)

  • Albert Hallsworth

    (The Institute of Cancer Research)

  • Vladimir Kirkin

    (The Institute of Cancer Research)

  • Kate Young

    (The Royal Marsden NHS Trust, London and Surrey)

  • Ruwaida Begum

    (The Royal Marsden NHS Trust, London and Surrey)

  • Andrew Wotherspoon

    (The Royal Marsden NHS Trust, London and Surrey)

  • Kyriakos Kouvelakis

    (The Royal Marsden NHS Trust, London and Surrey)

  • Sergio Xavier Azevedo

    (The Royal Marsden NHS Trust, London and Surrey)

  • Vasiliki Michalarea

    (The Royal Marsden NHS Trust, London and Surrey)

  • Rosie Upstill-Goddard

    (University of Glasgow)

  • Sheela Rao

    (The Royal Marsden NHS Trust, London and Surrey)

  • David Watkins

    (The Royal Marsden NHS Trust, London and Surrey)

  • Naureen Starling

    (The Royal Marsden NHS Trust, London and Surrey)

  • Anguraj Sadanandam

    (The Institute of Cancer Research)

  • David K. Chang

    (University of Glasgow
    West of Scotland Pancreatic Unit, Glasgow Royal Infirmary)

  • Andrew V. Biankin

    (University of Glasgow
    West of Scotland Pancreatic Unit, Glasgow Royal Infirmary
    South Western Sydney Clinical School, Faculty of Medicine, University of NSW)

  • Nigel B. Jamieson

    (University of Glasgow
    West of Scotland Pancreatic Unit, Glasgow Royal Infirmary)

  • Aldo Scarpa

    (, University of Verona)

  • David Cunningham

    (The Royal Marsden NHS Trust, London and Surrey)

  • Ian Chau

    (The Royal Marsden NHS Trust, London and Surrey)

  • Paul Workman

    (The Institute of Cancer Research)

  • Matteo Fassan

    (University of Padua
    Veneto Institute of Oncology (IOV-IRCCS))

  • Nicola Valeri

    (The Institute of Cancer Research
    The Royal Marsden NHS Trust, London and Surrey)

  • Chiara Braconi

    (The Institute of Cancer Research
    University of Glasgow
    The Royal Marsden NHS Trust, London and Surrey
    Beatson West of Scotland Cancer Centre)

Abstract

FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome.

Suggested Citation

  • Pietro Carotenuto & Francesco Amato & Andrea Lampis & Colin Rae & Somaieh Hedayat & Maria C. Previdi & Domenico Zito & Maya Raj & Vincenza Guzzardo & Francesco Sclafani & Andrea Lanese & Claudia Paris, 2021. "Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27099-6
    DOI: 10.1038/s41467-021-27099-6
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