2. Academic Validation
  3. PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma

PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma

  • Nat Commun. 2024 Feb 16;15(1):1446. doi: 10.1038/s41467-024-45760-8.
Abdallah Gaballa # 1,  Anneli Gebhardt-Wolf # 1,  Bastian Krenz 1 2,  Greta Mattavelli 2,  Mara John 2,  Giacomo Cossa 1,  Silvia Andreani 1,  Christina Schülein-Völk 3,  Francisco Montesinos 1,  Raphael Vidal 1 4,  Carolin Kastner 2,  Carsten P Ade 1,  Burkhard Kneitz 5,  Georg Gasteiger 6,  Peter Gallant 1,  Mathias Rosenfeldt 7,  Angela Riedel 2,  Martin Eilers 8 9
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biologyy, Theodor Boveri Institute, Biocenter, Julius Maximilian University Würzburg, Am Hubland, 97074, Würzburg, Germany.
  • 2 Mildred Scheel Early Career Center, University Hospital Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany.
  • 3 Core Unit High-Content Microscopy, Theodor Boveri Institute, Biocenter, Julius Maximilian University Würzburg, Am Hubland, 97074, Würzburg, Germany.
  • 4 Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany.
  • 5 Department of Urology and Pediatric Urology, University Hospital Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany.
  • 6 Würzburg Institute of Systems Immunology, Max Planck Research Group, Julius Maximilian University Würzburg, Versbacher Str. 9, 97078, Würzburg, Germany.
  • 7 Institute of Pathology, Julius Maximilian University Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany.
  • 8 Department of Biochemistry and Molecular Biologyy, Theodor Boveri Institute, Biocenter, Julius Maximilian University Würzburg, Am Hubland, 97074, Würzburg, Germany. martin.eilers@biozentrum.uni-wuerzburg.de.
  • 9 Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany. martin.eilers@biozentrum.uni-wuerzburg.de.
  • # Contributed equally.
PMID: 38365788 DOI: 10.1038/s41467-024-45760-8
Abstract

In pancreatic ductal adenocarcinoma (PDAC), endogenous MYC is required for S-phase progression and escape from immune surveillance. Here we show that MYC in PDAC cells is needed for the recruitment of the PAF1c transcription elongation complex to RNA polymerase and that depletion of CTR9, a PAF1c subunit, enables long-term survival of PDAC-bearing mice. PAF1c is largely dispensable for normal proliferation and regulation of MYC target genes. Instead, PAF1c limits DNA damage associated with S-phase progression by being essential for the expression of long genes involved in replication and DNA repair. Surprisingly, the survival benefit conferred by CTR9 depletion is not due to DNA damage, but to T-cell activation and restoration of immune surveillance. This is because CTR9 depletion releases RNA polymerase and elongation factors from the body of long genes and promotes the transcription of short genes, including MHC class I genes. The data argue that functionally distinct gene sets compete for elongation factors and directly link MYC-driven S-phase progression to tumor immune evasion.

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