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Updated: Jun 23, 2025
In Vivo CRISPR/Cas9 Screening to Simultaneously Evaluate Gene Function in Mouse Skin and Oral Cavity
Published on: November 2, 2020
In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer
Sebastien Martinez1, Shifei Wu1,2, Michael Geuenich1,2
1Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
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.
Insights
New research identifies USP15 and SCAF1 as crucial tumor suppressors in pancreatic cancer. Their loss impacts inflammatory responses and increases sensitivity to therapies like PARP inhibitors and Gemcitabine.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Understanding genetic alterations is key for pancreatic cancer precision medicine.
- Identifying novel tumor suppressors can reveal new therapeutic targets.
Purpose of the Study:
- To functionally characterize 125 recurrently mutated pancreatic cancer genes.
- To discover novel pancreatic tumor suppressors and their mechanisms of action.
Main Methods:
- Somatic CRISPR/Cas9 mutagenesis screens in vivo.
- Assessment of gene transforming potential in pancreatic cancer models.
- Analysis of inflammatory cytokine responses and drug sensitivity.
Main Results:
- USP15 and SCAF1 were identified as pancreatic tumor suppressors.
- Loss of USP15 or SCAF1 reduces inflammatory responses (TNFα, TGF-β, IL6) and enhances sensitivity to PARP inhibition and Gemcitabine.
- Loss of SCAF1 leads to a truncated, inactive USP15 isoform, linking their functions.
Conclusions:
- USP15 and SCAF1 alterations occur in 31% of pancreatic cancer patients.
- These findings highlight the utility of in vivo CRISPR screens for discovering cancer drivers.
- USP15 and SCAF1 have potential prognostic and therapeutic implications in pancreatic cancer.
