Thbs1 extracellular vesicles from irradiated tumors induce cardiac wasting via PERK-eIF2α-Atf4 signaling.

[AIMS] Cardiac muscle wasting is a significant complication observed in lung cancer patients receiving radiotherapy. Radiotherapy, a commonly used anticancer treatment, is known to cause cardiovascular complications; however, the mechanisms linking tumor irradiation to cardiac wasting remain poorly understood.

[METHODS] Lewis lung carcinoma (LLC) and CT26 tumor-bearing mice received localized tumor irradiation. Conditioned medium or EVs from irradiated tumor cells were collected and used to treat cardiomyocytes. Autophagy, protein synthesis, and atrophy were assessed. The roles of tumor Thbs1 and cardiac PERK signaling were determined via shRNA-mediated knockdown and PERK mutation in vitro and in vivo.

[RESULTS] We demonstrated that localized tumor irradiation induces cardiac muscle wasting in mice, which is associated with PERK-eIF2α-Atf4 pathway activation and increased Thbs1 protein-but not mRNA-levels in cardiomyocytes. Mechanistically, Thbs1 is delivered via extracellular vesicles (EVs) derived from irradiated tumors. Tumor-derived Thbs1 EVs are necessary and sufficient to trigger autophagy, suppress protein synthesis, and cause atrophy in cardiomyocytes, which is dependent on the Thbs1-PERK interaction and downstream signaling.

[CONCLUSION] These results indicate that radiotherapy promotes the release of Thbs1 EVs, which drive cardiac muscle wasting via PERK-eIF2α-Atf4 signaling, revealing a novel mechanism underlying cancer-associated cardiac damage.