2. Academic Validation
  3. Loss of p53 and SMAD4 induces adenosquamous subtype pancreatic cancer in the absence of an oncogenic KRAS mutation

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

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: ychen23@mdanderson.org.
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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