The importance of fusion protein activity in Ewing sarcoma and the cell intrinsic and extrinsic factors that regulate it: A review.

Autor:	Apfelbaum AA; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute and Department of Pediatrics, University of Washington, Seattle, WA, United States., Wrenn ED; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute and Department of Pediatrics, University of Washington, Seattle, WA, United States., Lawlor ER; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute and Department of Pediatrics, University of Washington, Seattle, WA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2022 Nov 24; Vol. 12, pp. 1044707. Date of Electronic Publication: 2022 Nov 24 (Print Publication: 2022).
DOI:	10.3389/fonc.2022.1044707
Abstrakt:	Accumulating evidence shows that despite clonal origins tumors eventually become complex communities comprised of phenotypically distinct cell subpopulations. This heterogeneity arises from both tumor cell intrinsic programs and signals from spatially and temporally dynamic microenvironments. While pediatric cancers usually lack the mutational burden of adult cancers, they still exhibit high levels of cellular heterogeneity that are largely mediated by epigenetic mechanisms. Ewing sarcomas are aggressive bone and soft tissue malignancies with peak incidence in adolescence and the prognosis for patients with relapsed and metastatic disease is dismal. Ewing sarcomas are driven by a single pathognomonic fusion between a FET protein and an ETS family transcription factor, the most common of which is EWS::FLI1. Despite sharing a single driver mutation, Ewing sarcoma cells demonstrate a high degree of transcriptional heterogeneity both between and within tumors. Recent studies have identified differential fusion protein activity as a key source of this heterogeneity which leads to profoundly different cellular phenotypes. Paradoxically, increased invasive and metastatic potential is associated with lower EWS::FLI1 activity. Here, we review what is currently understood about EWS::FLI1 activity, the cell autonomous and tumor microenvironmental factors that regulate it, and the downstream consequences of these activity states on tumor progression. We specifically highlight how transcription factor regulation, signaling pathway modulation, and the extracellular matrix intersect to create a complex network of tumor cell phenotypes. We propose that elucidation of the mechanisms by which these essential elements interact will enable the development of novel therapeutic approaches that are designed to target this complexity and ultimately improve patient outcomes. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Apfelbaum, Wrenn and Lawlor.)
Databáze:	MEDLINE
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