Maki Ryosuke, Iwagami Yoshifumi, Kobayashi Shogo, Sasaki Kazuki, Yamada Daisaku, Tomimaru Yoshito, Sakai Daisuke, Noda Takehiro, Asaoka Tadafumi, Takahashi Hidenori, Satoh Taroh, Shimizu Junzo, Doki Yuichiro, Eguchi Hidetoshi
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Department of Medical Oncology, Osaka International Cancer Institute, Osaka, Japan.
Ann Surg Oncol. 2025 May 30. doi: 10.1245/s10434-025-17482-8.
Mutations in TP53 are associated with a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated the relationship between TP53 mutations and lipid metabolism abnormalities caused by sterol O-acyltransferase 1 (SOAT1). We hypothesized that SOAT1 inhibitors would show high efficacy in patients with PDAC with TP53 mutations.
We performed SOAT1 immunohistochemistry staining of PDAC clinical tissue samples with next-generation sequencing-based comprehensive genomic profiling. We also confirmed the inhibitory effect of SOAT1 using siRNA and avasimibe in vitro and in vivo on pancreatic cancer cells of various TP53 states. We confirmed the mechanism using RNA sequencing analysis.
We identified a positive correlation between TP53 mutations and high SOAT1 expression. Notably, the prognosis of PDAC was worse in the presence of TP53 mutation than in the presence of wild-type TP53. Cell proliferation was more strongly suppressed in mutant p53 cells than in wild-type p53 and p53 null cells. Furthermore, we demonstrated that these observations were due to the presence of mutant p53 by adjusting the background via the introduction of mutant TP53. Antitumor efficacy resulting from SOAT1 inhibition was analyzed using RNA sequencing, and cell cycle suppression was observed only in mutant p53 cells.
Our results demonstrated that SOAT1 was upregulated in PDAC with TP53 mutations and that SOAT1 inhibition was more effective in TP53-mutated PDAC. These findings would aid in the development of targeted therapeutic strategies against PDAC with TP53 mutations.
TP53 突变与胰腺导管腺癌（PDAC）的预后不良相关。在本研究中，我们调查了 TP53 突变与由固醇 O-酰基转移酶 1（SOAT1）引起的脂质代谢异常之间的关系。我们假设 SOAT1 抑制剂对携带 TP53 突变的 PDAC 患者具有高效性。
我们对 PDAC 临床组织样本进行了 SOAT1 免疫组化染色，并结合基于下一代测序的综合基因组分析。我们还在体外和体内使用 siRNA 和阿伐麦布证实了 SOAT1 对各种 TP53 状态的胰腺癌细胞的抑制作用。我们通过 RNA 测序分析确定了其作用机制。
我们发现 TP53 突变与高 SOAT1 表达之间呈正相关。值得注意的是，存在 TP53 突变的 PDAC 患者的预后比存在野生型 TP53 的患者更差。与野生型 p53 和 p53 缺失的细胞相比，突变型 p53 细胞的增殖受到更强烈的抑制。此外，我们通过引入突变型 TP53 来调整背景，证明了这些观察结果是由于突变型 p53 的存在所致。使用 RNA 测序分析了 SOAT1 抑制产生的抗肿瘤疗效，并且仅在突变型 p53 细胞中观察到细胞周期抑制。
我们的结果表明，在携带 TP53 突变的 PDAC 中 SOAT1 上调，并且 SOAT1 抑制在 TP53 突变的 PDAC 中更有效。这些发现将有助于开发针对携带 TP53 突变的 PDAC 的靶向治疗策略。
