Cooperation between oncogenic Ras and wild-type p53 stimulates STAT non-cell autonomously to promote tumor radioresistance

Yong-Li Dong,Tian Xu,Lu-Fang Liu,Thomas J Klein,Gangadhara P Vadla,Peter M Glazer,Vakil Ahmad,Chiswili-Yves Chabu,Jin-Yu Jim Lu

doi:10.1038/s42003-021-01898-5

Abstract

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.

Highlights

Oncogenic RAS mutations are associated with tumor resistance to radiation therapy
RasV12 suppressor mutations are isolated through the identification of mutations that significantly reduce the clone size and rescue animal viability when introduced in RasV12-expressing cells[35]
Mutation 3804 potently suppresses RasV12-mediated tumor overgrowth and yields viable adult animals (Fig. 1a versus 1b; 1c versus 1d; 1g–l). To determine whether this mutation synthetically suppresses oncogenic Ras or is cell deleterious on its own, we generated wild-type or 3804 mutant clones in developing and adult eye tissues to determine whether this mutation synthetically suppresses oncogenic Ras or is deleterious to the cell itself

Summary

Introduction

Oncogenic RAS mutations are associated with tumor resistance to radiation therapy. Cell-cell interactions in the tumor microenvironment (TME) profoundly influence therapy outcomes. Cellular responses to DNA damage are complex and include activation of cell–cell interactions that we do not fully understand[24] How these nonautonomous effects influence the response of Ras-driven cancers to genotoxic therapies is an underexplored area of research. We found that ptip−/− causes genomic instability and upregulates dp[53] in RasV12 cells This upregulation of wild-type dp[53] cooperates with oncogenic Ras signaling to stimulate the secretion of JAK/STAT (Janus kinases/signal transducers and activators of transcription) ligands (interleukin 6-related cytokines known as unpaired in Drosophila). These ligands activate JAK/STAT in the surrounding cells, leading to tissue overgrowth. Blockade of any part of this p53/RasV12-STAT signaling relay inhibits the nonautonomous growth effect and resensitizes RasV12 tissues to IR treatment

Methods

Results

Conclusion