Targeting a chemo-induced adaptive signaling circuit confers therapeutic vulnerabilities in pancreatic cancer.

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2024-10-29 DOI:10.1038/s41421-024-00720-w
Yohei Saito, Yi Xiao, Jun Yao, Yunhai Li, Wendao Liu, Arseniy E Yuzhalin, Yueh-Ming Shyu, Hongzhong Li, Xiangliang Yuan, Ping Li, Qingling Zhang, Ziyi Li, Yongkun Wei, Xuedong Yin, Jun Zhao, Seyed M Kariminia, Yao-Chung Wu, Jinyang Wang, Jun Yang, Weiya Xia, Yutong Sun, Eek-Hoon Jho, Paul J Chiao, Rosa F Hwang, Haoqiang Ying, Huamin Wang, Zhongming Zhao, Anirban Maitra, Mien-Chie Hung, Ronald A DePinho, Dihua Yu
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引用次数: 0

Abstract

Advanced pancreatic ductal adenocarcinomas (PDACs) respond poorly to all therapies, including the first-line treatment, chemotherapy, the latest immunotherapies, and KRAS-targeting therapies. Despite an enormous effort to improve therapeutic efficacy in late-stage PDAC patients, effective treatment modalities remain an unmet medical challenge. To change the status quo, we explored the key signaling networks underlying the universally poor response of PDAC to therapy. Here, we report a previously unknown chemo-induced symbiotic signaling circuit that adaptively confers chemoresistance in patients and mice with advanced PDAC. By integrating single-cell transcriptomic data from PDAC mouse models and clinical pathological information from PDAC patients, we identified Yap1 in cancer cells and Cox2 in stromal fibroblasts as two key nodes in this signaling circuit. Co-targeting Yap1 in cancer cells and Cox2 in stroma sensitized PDAC to Gemcitabine treatment and dramatically prolonged survival of mice bearing late-stage PDAC, whereas simultaneously inhibiting Yap1 and Cox2 only in cancer cells was ineffective. Mechanistically, chemotherapy triggers non-canonical Yap1 activation by nemo-like kinase in 14-3-3ζ-overexpressing PDAC cells and increases secretion of CXCL2/5, which bind to CXCR2 on fibroblasts to induce Cox2 and PGE2 expression, which reciprocally facilitate PDAC cell survival. Finally, analyses of PDAC patient data revealed that patients who received Statins, which inhibit Yap1 signaling, and Cox2 inhibitors (including Aspirin) while receiving Gemcitabine displayed markedly prolonged survival compared to others. The robust anti-tumor efficacy of Statins and Aspirin, which co-target the chemo-induced adaptive circuit in the tumor cells and stroma, signifies a unique therapeutic strategy for PDAC.

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以化疗诱导的适应性信号回路为靶点,发现胰腺癌的治疗弱点。
晚期胰腺导管腺癌(PDAC)对所有疗法的反应都很差,包括一线疗法、化疗、最新的免疫疗法和 KRAS 靶向疗法。尽管为提高晚期 PDAC 患者的疗效做出了巨大努力,但有效的治疗方法仍是一项尚未解决的医学难题。为了改变现状,我们探索了 PDAC 对治疗普遍反应不佳的关键信号网络。在这里,我们报告了一种之前未知的化疗诱导共生信号回路,它能在晚期 PDAC 患者和小鼠中适应性地产生化疗抗性。通过整合 PDAC 小鼠模型的单细胞转录组数据和 PDAC 患者的临床病理信息,我们发现癌细胞中的 Yap1 和基质成纤维细胞中的 Cox2 是这一信号回路中的两个关键节点。联合靶向癌细胞中的 Yap1 和基质中的 Cox2 可使 PDAC 对吉西他滨治疗敏感,并显著延长晚期 PDAC 小鼠的存活时间,而仅同时抑制癌细胞中的 Yap1 和 Cox2 则无效。从机理上讲,化疗会在14-3-3ζ过表达的PDAC细胞中通过nemo-like激酶触发非经典的Yap1活化,并增加CXCL2/5的分泌,CXCL2/5与成纤维细胞上的CXCR2结合,诱导Cox2和PGE2的表达,从而相互促进PDAC细胞的存活。最后,对 PDAC 患者数据的分析表明,与其他患者相比,在接受吉西他滨治疗的同时接受他汀类药物(抑制 Yap1 信号转导)和 Cox2 抑制剂(包括阿司匹林)治疗的患者生存期明显延长。他汀类药物和阿司匹林共同针对肿瘤细胞和基质中化疗诱导的适应性回路,具有强大的抗肿瘤疗效,是治疗 PDAC 的独特疗法。
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 Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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