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

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2024-09-17 Epub Date: 2024-09-03 DOI:10.1016/j.xcrm.2024.101711

Daowei Yang, Xinlei Sun, Rohan Moniruzzaman, Hua Wang, Citu Citu, Zhongming Zhao, Ignacio I Wistuba, Huamin Wang, Anirban Maitra, Yang Chen

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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;Smad4^loxP/loxP;Pdx1-Cre (PPSSC) mouse model harbors KRAS-WT and loss of Trp53/Smad4. The Trp53^loxP/loxP;Tgfbr2^loxP/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.

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在没有致癌 KRAS 突变的情况下，p53 和 SMAD4 的缺失会诱发腺鳞癌亚型胰腺癌。

约 90% 的胰腺癌病例与致癌 KRAS 突变有关。然而，也有相当一部分胰腺癌病例携带野生型 KRAS（KRAS-WT）。这项研究建立了基因工程小鼠模型，这些小鼠在 KRAS-WT 的背景下发生自发性胰腺癌。Trp53loxP/loxP;Smad4loxP/loxP;Pdx1-Cre（PPSSC）小鼠模型携带 KRAS-WT 和 Trp53/Smad4 缺失。Trp53loxP/loxP;Tgfbr2loxP/loxP;Pdx1-Cre（PPTTC）小鼠模型携带 KRAS-WT 和 Trp53/Tgfbr2 缺失。我们发现，在没有致癌 KRAS 突变的情况下，Trp53/Smad4 缺失或 Trp53/Tgfbr2 缺失都能诱发自发性胰腺肿瘤的形成。与致癌 KRAS 驱动的小鼠模型相比，Trp53/Smad4 缺失和 Trp53/Tgfbr2 缺失小鼠模型表现出不同的胰腺肿瘤组织学特征。此外，Trp53/Smad4缺失的KRAS-WT胰腺肿瘤显示出胰腺腺鳞癌（PASC）的独特组织学特征。单细胞 RNA 测序（scRNA-seq）分析显示，与致癌 KRAS 驱动的胰腺肿瘤相比，KRAS-WT（PPSSC）胰腺肿瘤具有独特的肿瘤免疫微环境。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.