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In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer

Author

Listed:
  • Sebastien Martinez

    (Mount Sinai Hospital)

  • Shifei Wu

    (Mount Sinai Hospital
    University of Toronto)

  • Michael Geuenich

    (Mount Sinai Hospital
    University of Toronto)

  • Ahmad Malik

    (Mount Sinai Hospital
    University of Toronto)

  • Ramona Weber

    (University of Zurich)

  • Tristan Woo

    (University Health Network)

  • Amy Zhang

    (Ontario Institute for Cancer Research)

  • Gun Ho Jang

    (Ontario Institute for Cancer Research)

  • Dzana Dervovic

    (Mount Sinai Hospital)

  • Khalid N. Al-Zahrani

    (Mount Sinai Hospital)

  • Ricky Tsai

    (Mount Sinai Hospital)

  • Nassima Fodil

    (McGill University)

  • Philippe Gros

    (McGill University)

  • Steven Gallinger

    (Mount Sinai Hospital
    Ontario Institute for Cancer Research)

  • G. Gregory Neely

    (The University of Sydney)

  • Faiyaz Notta

    (University Health Network
    Ontario Institute for Cancer Research)

  • Ataman Sendoel

    (University of Zurich)

  • Kieran Campbell

    (Mount Sinai Hospital
    University of Toronto)

  • Ulrich Elling

    (Vienna BioCenter (VBC))

  • Daniel Schramek

    (Mount Sinai Hospital
    University of Toronto)

Abstract

Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as pancreatic tumor suppressors. Mechanistically, we find that USP15 functions in a haploinsufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-β and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine. Furthermore, we find that loss of SCAF1 leads to the formation of a truncated, inactive USP15 isoform at the expense of full-length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 alterations are observed in 31% of pancreatic cancer patients. Our results highlight the utility of in vivo CRISPR screens to integrate human cancer genomics and mouse modeling for the discovery of cancer driver genes with potential prognostic and therapeutic implications.

Suggested Citation

  • Sebastien Martinez & Shifei Wu & Michael Geuenich & Ahmad Malik & Ramona Weber & Tristan Woo & Amy Zhang & Gun Ho Jang & Dzana Dervovic & Khalid N. Al-Zahrani & Ricky Tsai & Nassima Fodil & Philippe G, 2024. "In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49450-3
    DOI: 10.1038/s41467-024-49450-3
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