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

Yong-Li Dong1,2, Gangadhara P Vadla3, Jin-Yu Jim Lu1,4

  • 1Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, New Haven, CT, USA.

Communications Biology
|March 20, 2021
PubMed

Insights

Oncogenic Ras mutations cause radiation resistance. A novel cell-cell communication pathway involving JAK/STAT signaling in the tumor microenvironment (TME) promotes tumor regrowth after radiation, suggesting new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Oncogenic RAS mutations are linked to tumor resistance to radiation therapy.
  • The tumor microenvironment (TME) significantly impacts therapy outcomes, but its role in Ras-driven radioresistance is not fully understood.

Purpose of the Study:

  • To investigate the mechanisms of cell-cell interactions in the TME that contribute to oncogenic Ras tumor radioresistance.
  • To identify potential therapeutic targets for overcoming Ras-driven radioresistance.

Main Methods:

  • Utilized Drosophila oncogenic Ras tissues and human Ras cancer cell radiation models.
  • Investigated the role of p53 activation and JAK/STAT signaling in response to genotoxic stress.
  • Examined the impact of blocking cell-cell communication pathways on tumor radioresistance.

Main Results:

  • Discovered that genotoxic stress and oncogenic Ras cooperate to activate non-cell autonomous JAK/STAT signaling in the TME.
  • Observed heterogeneous p53 activation in irradiated Ras tumor tissues, leading to cytokine stimulation.
  • Demonstrated that blocking this JAK/STAT communication loop re-sensitizes Ras tumors to irradiation.

Conclusions:

  • A novel cell-cell communication loop involving p53 and JAK/STAT signaling drives Ras tumor radioresistance.
  • Targeting this pathway, potentially with STAT inhibitors combined with radiotherapy, could improve treatment outcomes for Ras-driven cancers.

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