Complex Elucidation of Cells-of-Origin in Pediatric Soft Tissue Sarcoma: From Concepts to Real Life, Hide-and-Seek through Epigenetic and Transcriptional Reprogramming

Abstract

Soft tissue sarcoma (STS) comprise a large group of mesenchymal malignant tumors with heterogeneous cellular morphology, proliferative index, genetic lesions and, more importantly, clinical features. Full elucidation of this wide diversity remains a central question to improve their therapeutic management and the identity of cell(s)-of-origin from which these tumors arise is part of this enigma. Cellular reprogramming allows transitions of a mature cell between phenotypes, or identities, and represents one key driver of tumoral heterogeneity. Here, we discuss how cellular reprogramming mediated by driver genes in STS can profoundly reshape the molecular and morphological features of a transformed cell and lead to erroneous interpretation of its cell‑of‑origin. This review questions the fact that the epigenetic context in which a genetic alteration arises has to be taken into account as a key determinant of STS tumor initiation and progression. Retracing the cancer-initiating cell and its clonal evolution, notably via epigenetic approach, appears as a key lever for understanding the origin of these tumors and improving their clinical management.

Targeting epigenetic aberrations of sarcoma in CRISPR era

“…Despite the small number of patients with sarcoma, sarcomas are subdivided into more than 50 independent diseases, 1,2 making it difficult to clarify disease mechanisms and to develop effective therapies. Sarcomas develop from mesenchymal tissues, however, cells‐of‐origin remain to be clarified in many types of sarcomas, such as Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, epithelioid sarcoma, and extraskeletal myxoid chondrosarcoma 3–6 . Localized diseases of sarcoma are subjected to surgical resection, and additional chemotherapy and radiotherapy may be applied.…”

“…Sarcomas develop from mesenchymal tissues, however, cells-of-origin remain to be clarified in many types of sarcomas, such as Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, epithelioid sarcoma, and extraskeletal myxoid chondrosarcoma. [3][4][5][6] Localized diseases of sarcoma are subjected to surgical resection, and additional chemotherapy and radiotherapy may be applied. Many sarcomas affect young generations, and functional disabilities due to wide resection for localized diseases give rise to problems throughout life.…”