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

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 Gros, Steven Gallinger, G. Gregory Neely, Faiyaz Notta, Ataman Sendoel, Kieran Campbell, Ulrich Elling and Daniel Schramek ()
Additional contact information
Sebastien Martinez: Mount Sinai Hospital
Shifei Wu: Mount Sinai Hospital
Michael Geuenich: Mount Sinai Hospital
Ahmad Malik: Mount Sinai Hospital
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
G. Gregory Neely: The University of Sydney
Faiyaz Notta: University Health Network
Ataman Sendoel: University of Zurich
Kieran Campbell: Mount Sinai Hospital
Ulrich Elling: Vienna BioCenter (VBC)
Daniel Schramek: Mount Sinai Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49450-3

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DOI: 10.1038/s41467-024-49450-3

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