Loss of p53 and SMAD4 induces adenosquamous subtype pancreatic cancer in the absence of an oncogenic KRAS mutation

  • Cell Rep Med. 2024 Sep 17;5(9):101711. doi: 10.1016/j.xcrm.2024.101711.
Daowei Yang  1 ,  Xinlei Sun  1 ,  Rohan Moniruzzaman  2 ,  Hua Wang  3 ,  Citu Citu  4 ,  Zhongming Zhao  4 ,  Ignacio I Wistuba  5 ,  Huamin Wang  6 ,  Anirban Maitra  1 ,  Yang Chen  7
Affiliations
  • 1. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 2. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 3. Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 4. Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  • 5. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 6. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 7. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 39232498 DOI: 10.1016/j.xcrm.2024.101711
Abstract

Pancreatic Cancer is associated with an oncogenic KRAS mutation in approximately 90% of cases. However, a non-negligible proportion of pancreatic Cancer cases harbor wild-type KRAS (KRAS-WT). This study establishes genetically engineered mouse models that develop spontaneous pancreatic Cancer in the context of KRAS-WT. The Trp53loxP/loxP;Smad4loxP/loxP;Pdx1-Cre (PPSSC) mouse model harbors KRAS-WT and loss of Trp53/SMAD4. The Trp53loxP/loxP;Tgfbr2loxP/loxP;Pdx1-Cre (PPTTC) mouse model harbors KRAS-WT and loss of Trp53/Tgfbr2. We identify that either Trp53/SMAD4 loss or Trp53/Tgfbr2 loss can induce spontaneous pancreatic tumor formation in the absence of an oncogenic KRAS mutation. The Trp53/SMAD4 loss and Trp53/Tgfbr2 loss mouse models exhibit distinct pancreatic tumor histological features, as compared to oncogenic KRAS-driven mouse models. Furthermore, KRAS-WT pancreatic tumors with Trp53/SMAD4 loss reveal unique histological features of pancreatic adenosquamous carcinoma (PASC). Single-cell RNA Sequencing (scRNA-seq) analysis reveals the distinct tumor immune microenvironment landscape of KRAS-WT (PPSSC) pancreatic tumors as compared with that of oncogenic KRAS-driven pancreatic tumors.

Keywords
genetically engineered mouse models; pancreatic adenosquamous carcinoma; pancreatic ductal adenocarcinoma; single-cell RNA-sequencing analysis; tumor microenvironment.
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