Overcoming Wnt-β-catenin dependent anticancer therapy resistance in leukaemia stem cells.,Nature Cell Biology

当前位置： X-MOL 学术 › Nat. Cell Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Overcoming Wnt-β-catenin dependent anticancer therapy resistance in leukaemia stem cells.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-04-20 , DOI: 10.1038/s41556-020-0507-y
John M Perry _{1,

2,

3,

4} , Fang Tao _{1,

2} , Anuradha Roy ₅ , Tara Lin ₃ , Xi C He ₁ , Shiyuan Chen ₁ , Xiuling Lu ₆ , Jacqelyn Nemechek ₂ , Linhao Ruan _{1,

7} , Xiazhen Yu _{1,

8} , Debra Dukes ₁ , Andrea Moran ₁ , Jennifer Pace ₂ , Kealan Schroeder ₂ , Meng Zhao _{1,

9} , Aparna Venkatraman ₁ , Pengxu Qian _{1,

10,

11} , Zhenrui Li _{1,

12} , Mark Hembree ₁ , Ariel Paulson ₁ , Zhiquan He ₁₃ , Dong Xu ₁₃ , Thanh-Huyen Tran _{6,

14} , Prashant Deshmukh ₁₅ , Chi Thanh Nguyen ₁₆ , Rajeswari M Kasi _{15,

16} , Robin Ryan ₂ , Melinda Broward ₃ , Sheng Ding ₁₇ , Erin Guest ₂ , Keith August ₂ , Alan S Gamis ₂ , Andrew Godwin ₃ , G Sitta Sittampalam _{3,

18} , Scott J Weir ₁₉ , Linheng Li _{1,

20}

Affiliation

Stowers Institute for Medical Research, Kansas City, MO, USA.
Children's Mercy Kansas City, Kansas City, MO, USA.
University of Kansas Medical Center, Kansas City, KS, USA.
University of Missouri Kansas City School of Medicine, Kansas City, MO, USA.
High Throughput Screening Laboratory, University of Kansas, Lawrence, KS, USA.
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA.
Center for Cell Dynamics, Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China.
Center of Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
St. Jude, Memphis, TN, USA.
Department of Electrical Engineering and Computer Science and C.S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.
Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, US.
Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT, USA.
Department of Chemistry, University of Connecticut, Storrs, CT, USA.
School of Pharmaceutical Science, Tsinghua University, Beijing, China.
Therapeutics for Rare and Neglected Diseases, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Department of Cancer Biology, The Institute for Advancing Medical Innovation and University of Kansas Cancer Center, Kansas City, Kansas, USA.
Department of Pathology and Laboratory Medicine and Division of Medical Oncology, Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt-β-catenin and PI3K-Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt-β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.

中文翻译：

克服白血病干细胞中的 Wnt-β-catenin 依赖性抗癌治疗耐药性。

白血病干细胞（LSC）是癌症治疗耐药性的基础，但靶向这些细胞仍然很困难。 Wnt-β-catenin 和 PI3K-Akt 通路协同促进肿瘤发生和治疗耐药。在干细胞和祖细胞中两条通路均被激活的小鼠模型中，LSC 在化疗引起的应激下扩增。由于 Akt 可以激活 β-连环蛋白，因此抑制这种相互作用可能会针对治疗耐药的 LSC。高通量筛选确定阿霉素 (DXR) 是低剂量 Akt-β-连环蛋白相互作用的抑制剂。在这里，我们将 DXR 重新定位为靶向抑制剂，而不是广泛的细胞毒性化疗。靶向 DXR 降低了化疗耐药 LSC 中 Akt 激活的 β-连环蛋白水平，并降低了 LSC 致瘤活性。从机制上讲，β-连环蛋白结合多个免疫检查点基因位点，靶向 DXR 治疗可抑制 LSC 中多个免疫检查点的表达，包括 PD-L1、TIM3 和 CD24。总体而言，LSC 表现出独特的免疫抵抗特性，通过抑制 Akt 激活的 β-连环蛋白可以降低免疫抵抗力。这些发现提出了克服癌症治疗耐药性和免疫逃逸的策略。

更新日期：2020-04-24

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11