Xiao Zhang

Sarcomas are rare, genomically heterogeneous malignancies for which prognosis has remained poor and largely unchanged over recent decades. Patient‐derived xenograft (PDX) models are an important tool for cancer research, but their availability and utility remain limited in sarcoma. Here, we establish the SGH sarcoma PDX biobank, a living multi‐omics resource comprising 155 xenografts from 132 patients across 11 sarcoma histotypes, with osteosarcoma as the predominant subtype. This cohort is enriched for high‐risk sarcomas characterized by poor prognosis and widespread copy‐number alterations. Using this biobank, we show that extrachromosomal DNA (ecDNA) frequently drives high‐level oncogene amplification in osteosarcoma and that MYC ecDNA may underlie aggressive disease trajectories. Analyses of paired patient and PDX samples demonstrate that ecDNA is preferentially retained over intrachromosomal amplicons during engraftment and is stably maintained in PDX models. In addition, the PDX models largely recapitulate the histopathological and molecular features of their matched patient tumors while exhibiting distinct clonal evolutionary trajectories during engraftment. Finally, we identified potentially actionable genomic alterations within this PDX cohort, demonstrated genotype‐matched targeted therapy in a KRAS G12C‐mutant PDX model, and prioritized several candidate antibody–drug conjugate targets. Together, this resource provides a platform for biological discovery and preclinical precision oncology for sarcoma.

BACKGROUND: Extracellular vesicles (EVs) are involved in exercise-induced cardiac protection. However, the effects and underlying mechanisms of tissue-specific molecular cargo packaged within these EVs, including PIWI (P-element induced wimpy testis)-interacting RNA (piRNA), remain poorly understood. In particular, the mechanistic contribution of exercised intracardiac EV-associated piRNAs to doxorubicin-induced cardiotoxicity (DCT) has not been defined. METHODS: Transgenic reporter mice and a cardiomyocyte-specific Rab27a (RAB27A, member RAS oncogene family) knockout strategy were used to investigate the contribution of cardiomyocyte-derived EVs to exercise-induced cardioprotection against DCT. To screen functionally relevant cardioprotective piRNA cargo, heart tissues from patients with dilated cardiomyopathy and experimental DCT models were analyzed, including cardiomyocyte-specific knockout mice, human embryonic stem cell–derived cardiomyocytes, and primary murine cardiomyocytes. RESULTS: We found that cardiomyocyte-derived EVs post-exercise were enriched for a cardiac-specific protective piRNA (piR-mmu-57256903), designated as an exercise-induced protective piRNA (EPPIR). EPPIR levels were significantly reduced in heart tissue from patients with dilated cardiomyopathy and DCT models. Functionally, EPPIR protects the heart against DCT by regulating KDM6B (lysine [K]-specific demethylase 6B)-H3K27me3 (trimethylated histone H3 at lysine 27)-Dtna epigenetic axis. In addition, EPPIR acts as a cardiomyocyte-specific suppressor of Tp53 (tumor protein p53). CONCLUSIONS: We identify a previously unrecognized role for cardiomyocyte-derived EV-associated piRNA EPPIR in mediating exercise-induced cardioprotection. EPPIR exerts its protective effects through coordinated regulation of the KDM6B-Dtna axis and cardiomyocyte-specific suppressor of Tp53, providing mechanistic insight and highlighting a potential therapeutic strategy for DCT.