It is contracting: Physics meets Ewing sarcoma biology

Sarcomas are rare but devastating cancers that predominantly affect children and young adults. Arising in bone and/or soft tissues, they account for roughly one-fifth of all childhood malignancies. Among them, Ewing sarcoma is one of the most aggressive subtypes, characterized by limited treatment options and poor patient survival. Unlike most cancers of the elderly, which typically develop gradually through the accumulation of numerous genetic alterations, Ewing sarcoma often originates from a single chromosomal translocation that produces a fusion oncogene - most commonly EWSR1::FLI1. The rarity of sarcomas, despite their origin in abundant tissue types and the frequent occurrence of catastrophic genome rearrangements, poses a fundamental question: why do only certain cells undergo malignant transformation, while others harboring the same genetic lesion dont? This project explores a new idea that may hold the answer - the role of mechanical forces in cancer formation. During normal development, tissues in the body experience constant mechanical stimulation from muscle contractions. These physical cues shape organs, control how cells specialize, and even influence gene activity. We propose that such forces may also determine whether a cell harboring an oncogenic fusion protein ultimately becomes malignant. Specifically, we suggest that the elusive third hit required for tumor initiation - alongside the fusion oncogene and its cellular context - may not be genetic in nature, but mechanical. To test this concept, we will use a cutting-edge model called a neuromuscular organoid - a miniature, self-organizing tissue grown from human stem cells that contains both muscle and nerve cells and can contract spontaneously. By introducing the Ewing sarcoma fusion oncogene into these organoids, we can observe how muscle contractions and their strength affect the behavior of potential tumor cells. We will then analyze how mechanical activity reshapes their structure, gene expression, and ability to form tumor-like tissue. This approach bridges the fields of physics, developmental biology, and cancer genomics, opening a new dimension in the study of pediatric cancers investigating how physical forces can drive or prevent cancer development. Ultimately, this project aims to uncover the fundamental mechanical principles that govern tumor formation in childhood cancers. The findings could lay the groundwork for a new type of mechanomedicine, in which therapies target not only genes and molecules but also the physical environment of cancer cells. By advancing our understanding of how tissues sense and respond to mechanical stress, this work may inspire novel, gentler, and more effective strategies to treat sarcomas and improve outcomes for young patients facing this aggressive disease.