NFATc1/SMAD3/cJUN 复合物仅限于 SMAD4 缺陷的胰腺癌，可指导合理的治疗。
An NFATc1/SMAD3/cJUN complex restricted to SMAD4-deficient pancreatic cancer guides rational therapies.
发表日期：2023 Oct 30
作者：
Marie C Hasselluhn, Denise Schlösser, Lennart Versemann, Geske E Schmidt, Maria Ulisse, Joana Oschwald, Zhe Zhang, Feda Hamdan, Harry Xiao, Waltraut Kopp, Jessica Spitalieri, Christin Kellner, Carolin Schneider, Kristina Reutlinger, Sankari Nagarajan, Benjamin Steuber, Stephen A Sastra, Carmine F Palermo, Jennifer Appelhans, Hanibal Bohnenberger, Jovan Todorovic, Irina Kostyuchek, Philipp Ströbel, Aiko Bockelmann, Alexander König, Christoph Ammer-Herrmenau, Laura Schmidleitner, Silke Kaulfuß, Bernd Wollnik, Stephan A Hahn, Albrecht Neesse, Shiv K Singh, Holger Bastians, Maximilian Reichert, Ulrich Sax, Kenneth P Olive, Steven A Johnsen, Günter Schneider, Volker Ellenrieder, Elisabeth Hessmann
来源：
Epigenetics & Chromatin
摘要：
胰腺导管腺癌 (PDAC) 的高度异质性细胞和分子组成不仅促进了异常侵袭性的肿瘤生物学，而且与当前对抗 PDAC 的“一刀切”治疗策略的概念相矛盾。因此，我们的目的是探索临床相关分子 PDAC 亚群的肿瘤生物学意义和治疗脆弱性，该亚群以 SMAD4 缺陷和活化 T 细胞核因子 (SMAD4-/-/NFATc1High) 高表达为特征。转录组学和临床数据进行分析以确定 SMAD4-/-/NFATc1High 癌症的预后相关性。通过免疫沉淀、邻近连接测定以及验证的交叉模型和物种来研究体外和体内致癌转录因子复合物的形成。 SMAD4 状态对治疗靶向经典 KRAS 信号传导的影响分别通过全基因组基因表达分析和遗传扰动实验从机制上破译和证实。在源自患者的类器官和细胞以及转基因和原位 PDAC 模型中对新型定制治疗方案进行了验证。我们的研究结果确定了侵袭性和化疗耐药性 SMAD4-/-/NFATc1High 亚组的肿瘤生物学。从机制上讲，我们认为 SMAD4 缺陷是形成致癌 NFATc1/SMAD3/cJUN 转录因子复合物的分子先决条件，该复合物驱动 RRM1/2 的表达。 RRM1/2 补充核苷池，直接与代谢的吉西他滨竞争 DNA 链掺入。通过丝裂原激活蛋白激酶信号传导抑制 (MEKi) 分解 NFATc1/SMAD3/cJUN 复合物可使 RRM1/2 表达正常化，并与体内吉西他滨治疗协同降低增殖指数。我们的结果表明，PDAC 以 SMAD4 缺陷和致癌 NFATc1 为特征。 /SMAD3/cJUN 复合物的形成暴露了对 MEKi/吉西他滨联合疗法的敏感性。版权所有 © 2023 AGA Institute。由爱思唯尔公司出版。保留所有权利。
The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology but contradicts the current concept of one size fits all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and the therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the Nuclear Factor of Activated T-cells (SMAD4-/-/NFATc1High).Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of the SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models.Our findings determine the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition (MEKi) normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index.Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a MEKi/gemcitabine combination therapy.Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.