Intratumor heterogeneity and clonal evolution in sarcomas: Molecular, cellular, and functional drivers of therapy resistance

Sarcomas, malignant neoplasms of mesenchymal origin, comprise more than 100 entities and numerous histologic subtypes. Their relative rarity compared with carcinomas, interpatient diversity, and pronounced intratumor heterogeneity (ITH) make sarcomas clinically challenging. Yet, they also provide excellent models for studying the molecular and cellular underpinnings of ITH and how it translates into diverse clinical outcomes. New single-cell and spatial omics technologies have revealed the complex architecture of sarcomas with unprecedented resolution. In this review, we use five representative entities - two genomically complex (osteosarcoma, dedifferentiated liposarcoma) and three fusion-driven, genomically "quieter" (Ewing sarcoma, synovial sarcoma, alveolar rhabdomyosarcoma) sarcomas - to showcase recent advances in the field of ITH and the temporal evolution of sarcomas. Specifically, we review how clonal and subclonal molecular alterations, fluctuations in oncogene activity and other forms of cellular plasticity, as well as the formation of complex intratumor ecosystems, drive sarcoma progression and shape therapy resistance. We also provide an overview of recent advances in modeling ITH in sarcomas, as well as in evaluating functional diversity and assessing patient-specific treatment responses. Finally, we outline future directions in ITH research and its clinical implications.