Work

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

Year: 2025

Type: article

Abstract: • Tumor irradiation releases Thbs1 + EVs causing cardiac atrophy. • Thbs1 + EVs activate PERK-eIF2α-Atf4 signaling in cardiomyocytes. • EV-Thbs1 binding to PERK induces autophagy & suppresses protein synthesis. • Blocking tumor Thbs1 or cardiomyocyte PERK prevents radiation-induced cardiac wasting. 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. 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 HL-1 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 . 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. 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.

Source: Journal of Advanced Research

DOI: 10.1016/j.jare.2025.12.053