| Autor: |
Vakil Ahmad, Peter M. Glazer, Ganghadara P Valdka, Lu-Fang Liu, Tian Xu, Chiswili Yves Chabu, Jin-Yu Lu, Thomas J. Klein, Yongli Dong |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.10.05.327098 |
| Popis: |
Oncogenic RAS mutations are associated with tumor resistance to radiation therapy. The underlying mechanisms remain unclear. Emergent cell-cell interactions in the tumor microenvironment (TME) profoundly influence therapy outcomes. The nature of these interactions and their role in Ras tumor radioresistance remain unclear. We usedDrosophilaoncogenic Ras tissues and human Ras cancer cell radiation models to address these questions. We discovered that cellular response to genotoxic stress cooperates with oncogenic Ras to activate JAK/STAT non-cell autonomously in the TME. JAK/STAT accelerates the growth of the less-damaged Ras tumor cells, leading to rapid tumor recurrence. 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. This finding suggests that coupling STAT inhibitors to radiotherapy might improve clinical outcomes for Ras cancer patients. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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