Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, New Haven, CT, USA.
State Key Laboratory of Genetic Engineering and National Center for International Research, Fudan-Yale Biomedical Research Center, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China.
Commun Biol. 2021 Mar 19;4(1):374. doi: 10.1038/s42003-021-01898-5.
Oncogenic RAS mutations are associated with tumor resistance to radiation therapy. Cell-cell interactions in the tumor microenvironment (TME) profoundly influence therapy outcomes. However, the nature of these interactions and their role in Ras tumor radioresistance remain unclear. Here we use Drosophila oncogenic Ras tissues and human Ras cancer cell radiation models to address these questions. We discover that cellular response to genotoxic stress cooperates with oncogenic Ras to activate JAK/STAT non-cell autonomously in the TME. Specifically, p53 is heterogeneously activated in Ras tumor tissues in response to irradiation. This mosaicism allows high p53-expressing Ras clones to stimulate JAK/STAT cytokines, which activate JAK/STAT in the nearby low p53-expressing surviving Ras clones, leading to robust tumor re-establishment. Blocking any part of this cell-cell communication loop re-sensitizes Ras tumor cells to irradiation. These findings suggest that coupling STAT inhibitors to radiotherapy might improve clinical outcomes for Ras cancer patients.
致癌 RAS 突变与肿瘤对放射治疗的抵抗有关。肿瘤微环境（TME）中的细胞间相互作用深刻地影响治疗结果。然而，这些相互作用的性质及其在 Ras 肿瘤放射抵抗中的作用仍不清楚。在这里，我们使用果蝇致癌 Ras 组织和人类 Ras 癌症细胞放射模型来解决这些问题。我们发现，细胞对遗传毒性应激的反应与致癌 Ras 合作，非自主地在 TME 中激活 JAK/STAT。具体来说，p53 在受到照射后在 Ras 肿瘤组织中呈现异质性激活。这种镶嵌现象允许高表达 p53 的 Ras 克隆刺激 JAK/STAT 细胞因子，这些细胞因子激活附近低表达 p53 的存活 Ras 克隆中的 JAK/STAT，导致强大的肿瘤重建。阻断这个细胞间通讯循环的任何部分都能使 Ras 肿瘤细胞对辐射重新敏感。这些发现表明，将 STAT 抑制剂与放射治疗相结合可能会改善 Ras 癌症患者的临床结果。
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