尽管 KRAS 和 PI3K 通路的异常激活以及 TP53 突变导致人类胃癌中频繁出现异常，但这些突变的序列和个体贡献均尚未阐明。在这里，我们建立了一系列等位基因小鼠，以在腺上皮中条件性表达 KrasG12D；Pik3caH1047R 或 Trp53R172H 和/或 Pten 或 Trp53 的消融。我们发现 KrasG12D;Pik3caH1047R 足以诱发腺瘤，并且当也含有 Pten 缺失时，病变会进展为癌。 Trp53 功能丧失或获得功能等位基因的额外挑战进一步加速了肿瘤进展并引发转移性疾病。虽然响应 gp130 家族细胞因子的肿瘤内在 STAT3 信号传导仍然是肿瘤发展所有阶段的看门人，但转移进展需要突变 Trp53 诱导的白细胞介素 (IL)-11 到 IL-6 依赖性转换。与 IL-6 高表达患者的生存率较差相一致，我们确定 IL-6/STAT3 信号传导是 TP53 突变型胃癌的治疗脆弱性。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of KrasG12D;Pik3caH1047R or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047R is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions. An additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with the poorer survival of patients with high IL-6 expression, we identify IL-6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.