Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus

Area of Science:

• Oncology
• Genetics
• Immunology

Background:

• The ATRX gene is frequently altered in solid tumors, particularly soft tissue sarcomas.
• The specific role of ATRX in tumor development and its impact on cancer therapy response are not well understood.

Purpose of the Study:

• To investigate the role of ATRX in soft tissue sarcoma development and its sensitivity to cancer therapies.
• To elucidate the mechanisms underlying ATRX's influence on tumor response to radiation and oncolytic viruses.

Main Methods:

• Development of a primary mouse model of soft tissue sarcoma with Atrx deletion.
• Analysis of DNA damage, telomere dysfunction, and mitotic catastrophe in irradiated Atrx-deleted sarcomas.
• Assessment of the CGAS/STING signaling pathway and adaptive immune response in Atrx-deleted sarcoma models.
• Evaluation of tumor sensitivity to radiation therapy and oncolytic herpesvirus (TVEC).

Main Results:

• Atrx-deleted sarcomas exhibited increased sensitivity to radiation therapy and oncolytic herpesvirus.
• Absence of ATRX led to persistent DNA damage, telomere dysfunction, and mitotic catastrophe in irradiated tumors.
• Atrx deletion resulted in downregulation of the CGAS/STING signaling pathway and a reduced adaptive immune response.
• Both human and mouse Atrx-deleted sarcoma models showed impaired CGAS/STING signaling and heightened sensitivity to TVEC.

Conclusions:

• ATRX deletion in soft tissue sarcomas enhances sensitivity to radiation and oncolytic viral therapy.
• The impaired CGAS/STING signaling and reduced immune response in Atrx-deleted tumors contribute to increased therapy sensitivity.
• These findings suggest potential for genomically guided cancer therapies targeting ATRX-mutant cancers.