1. Loss of p53 and SMAD4 induces adenosquamous subtype pancreatic cancer in the absence of an oncogenic KRAS mutation.
- Author
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Yang D, Sun X, Moniruzzaman R, Wang H, Citu C, Zhao Z, Wistuba II, Wang H, Maitra A, and Chen Y
- Subjects
- Animals, Mice, Humans, Carcinoma, Adenosquamous genetics, Carcinoma, Adenosquamous pathology, Carcinoma, Adenosquamous metabolism, Disease Models, Animal, Receptor, Transforming Growth Factor-beta Type II genetics, Receptor, Transforming Growth Factor-beta Type II metabolism, Smad4 Protein genetics, Smad4 Protein metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Proto-Oncogene Proteins p21(ras) genetics, Mutation genetics
- 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 Trp53
loxP/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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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