Madelyn Espinosa-Cotton
Sean B. Lee
Anand G. Patel- 1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
- 2Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United States
- 3Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, United States
- 4Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, United States
Editorial on the Research Topic
New strategies for treating fusion-driven sarcomas
Sarcomas are rare connective tissue tumors that resemble a wide range of histologies including bone, fat, muscle, nerve and blood vessels. Among sarcomas, a subset of tumors harbors a fusion oncogene that drives transformation and malignant progression. These fusion-driven sarcomas have proven to be challenging to treat, and overall survival for patients with fusion-driven sarcomas remains low especially for patients with relapsed or disseminated disease. These poor patient outcomes underscore the critical need for a better understanding of the unique molecular and cellular biology of fusion-driven sarcomas, and for concerted efforts to develop therapies targeted against these tumors.
In this Research Topic, we have compiled five articles focused on the biology of fusion-driven sarcoma and on emerging targets for the treatment of these diseases. Each article or review addresses important and emerging concepts in the study of these rare cancers. Importantly, they shed light on molecular pathways that may be exploitable for future therapeutic benefit.
In a review, Gustafson et al. discuss the ongoing challenge of rhabdomyosarcoma, a sarcoma that mimics the morphologic and molecular features of developing skeletal muscle (Skapek et al., 2019). Recent single-cell sequencing efforts have elucidated the surprising degree of embryonal patterning from muscle development that is preserved in malignant rhabdomyosarcoma cells, which have recently been consolidated into a standardized nomenclature (Danielli et al., 2024). While rhabdomyosarcoma cells mimic much of early muscle development, they fail to terminally differentiate, and fusion-positive rhabdomyosarcomas exhibit an unexpected plasticity to convert into a neuronal-like identity (Danielli et al., 2024). Despite these advances, much remains to be uncovered–namely, how rhabdomyosarcoma cells undergo transitions between cell states and how those cell states are regulated. Gustafson et al. present the latest understanding of core regulatory circuitry within both fusion-negative and fusion-positive rhabdomyosarcoma and identify emerging tools to target transcriptional circuits.
In a perspective, Stanton and Pomella present a comprehensive overview of the epigenetic drivers within fusion-driven sarcomas. Most of these entities are driven by translocations of two transcription factors; as such, understanding the dysregulation of core regulatory circuits remains a critical goal for advancing our understanding of this disease. The authors present a holistic view for a translational research approach that integrates discovery-based analysis of clinical samples with experimental modeling to uncover how fusion oncogenes drive epigenetic reprogramming in these cancers. Complementary to this review, a perspective by Ponce et al. focuses on a rare but fascinating subtype of sarcoma driven by CIC-rearrangements. These tumors, which were originally categorized as “Ewing-like tumors” have emerged as distinct entities through exhaustive analysis of patient samples (Antonescu et al., 2017; Specht et al., 2014; Kawamura-Saito et al., 2006). The authors summarize current work and emerging models for studying CIC rearranged tumors, and they single out major barriers limiting progress.
Excitingly, this Research Topic includes two original research articles uncovering new therapeutic approaches to treating fusion-driven sarcomas. Lee et al. test novel agents targeting topoisomerase I in Ewing sarcoma models. While camptothecins analogs, such as irinotecan, are often used in many relapsed Ewing sarcoma regimens (Casey et al., 2009; Raciborska et al., 2013), complex pharmacokinetics and toxicity have been barriers to their utility. Using a novel class of agents called indenoisoquinolines, which are long-lived trappers of topoisomerase I, the authors show that they can achieve growth suppression of Ewing sarcoma models in vitro and in vivo. In the other article, Parker et al. test the strategy of combining FYN inhibitors, which target a downstream target of the driver SS18:SSX fusion, with histone deacetylase inhibitors in synovial sarcoma. The enhanced therapeutic outcome of the dual targeting approach presents a conceptual framework for targeting fusion oncoproteins via their direct downstream targets.
While this Research Topic has collected a diverse set of articles, it also reinforces important questions about fusion-driven sarcomas and outlines key barriers that limit our ability to study these diseases. While it is clear that fusion oncogenes can drive expression of aberrant gene expression programs, it remains unclear why there is such a tissue and histologic specificity for each fusion. For example, translocations between EWSR1 and FLI1 are typical of Ewing sarcoma, while EWSR1::ATF1 fusions drive clear cell sarcoma. To understand lineage specific tolerance and transformation, well-credentialed experimental models are needed. Recent work developing zebrafish models of VGLL2::NCOA1 driven rhabdomyosarcoma may demonstrate a powerful approach for modeling malignant transformation in vivo (Watson et al., 2023). Likewise, induced pluripotent stem cells and somatic gene delivery using electroporation have presented new opportunities to control oncogene activation at varying developmental states (Searcy et al., 2023; Imle et al., 2024). Lastly, our field needs a systematic approach to understand the most effective strategy for targeting fusion oncogenes. There are active efforts to target the oncogenes themselves, which has been a major challenge, or as Parker et al. demonstrate, by using inhibitors against druggable targets directly downstream of the fusion oncogene itself. Collectively, the field of fusion-driven sarcomas is poised to make a long-awaited step forward.
Author contributions
ME-C: Writing – review and editing, Writing – original draft. SL: Writing – original draft, Writing – review and editing. AP: Writing – review and editing, Writing – original draft.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Acknowledgments
We thank the contributor authors and reviewers for their hard work on this Research Topic.
Conflict of interest
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.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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References
Antonescu, C. R., Owosho, A. A., Zhang, L., Chen, S., Deniz, K., Huryn, J. M., et al. (2017). Sarcomas with CIC-Rearrangements are a distinct Pathologic entity with Aggressive outcome: a Clinicopathologic and molecular study of 115 Cases. Am. J. Surg. Pathol. 41 (7), 941–949. doi:10.1097/PAS.0000000000000846
Casey, D. A., Wexler, L. H., Merchant, M. S., Chou, A. J., Merola, P. R., Price, A. P., et al. (2009). Irinotecan and Temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr. Blood Cancer 53 (6), 1029–1034. doi:10.1002/pbc.22206
Danielli, S. G., Yun, W., Dyer, M. A., Stewart, E., Sheppard, H., Wachtel, M., et al. (2024). Single cell Transcriptomic Profiling Identifies Tumor-Acquired and Therapy-Resistant cell states in tediatric rhabdomyosarcoma. Nat. Commun. 15 (1), 6307. doi:10.1038/s41467-024-50527-2
Imle, R., Blosel, D., Felix, K. K. F., Eric Zhao, S., Autry, R., Blume, C., et al. (2024). Somatic gene delivery for Flexible in vivo modeling of eigh-misk sarcoma. BioRxiv. doi:10.1101/2024.01.30.577924
Kawamura-Saito, M., Yamazaki, Y., Kaneko, K., Kawaguchi, N., Kanda, H., Mukai, H., et al. (2006). Fusion between CIC and DUX4 Up-segulates PEA3 kamily genes in Ewing-like sarcomas with t(4;19)(t13) translocation. Hum. Mol. Genet. 15 (13), 2125–2137. doi:10.1093/hmg/ddl136
Raciborska, A., Bilska, K., Drabko, K., Chaber, R., Pogorzala, M., Wyrobek, E., et al. (2013). Vincristine, irinotecan, and Temozolomide in patients with relapsed and pefractory Ewing sarcoma. Pediatr. Blood Cancer 60 (10), 1621–1625. doi:10.1002/pbc.24621
Searcy, M. B., Larsen, R. K., Stevens, B. T., Zhang, Y., Jin, H., Drummond, C. J., et al. (2023). PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors. Nat. Commun. 14 (1), 7291. doi:10.1038/s41467-023-43044-1
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Specht, K., Sung, Y.-S., Zhang, L., Richter, G. H. S., Fletcher, C. D., and Antonescu, C. R. (2014). Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged ewing sarcomas: further evidence toward distinct pathologic entities. Genes, Chromosom. Cancer 53 (7), 622–633. doi:10.1002/gcc.22172
Keywords: sarcoma, fusion oncogene, treatment, epigenetics, intratumoral heterogeneity
Citation: Espinosa-Cotton M, Lee SB and Patel AG (2025) Editorial: New strategies for treating fusion-driven sarcomas. Front. Cell Dev. Biol. 13:1600133. doi: 10.3389/fcell.2025.1600133
Received: 25 March 2025; Accepted: 27 March 2025;
Published: 03 April 2025.
Edited and reviewed by:
Shyamala Maheswaran, Massachusetts General Hospital and Harvard Medical School, United StatesCopyright © 2025 Espinosa-Cotton, Lee and Patel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Madelyn Espinosa-Cotton, ZXNwaW5vbTFAbXNrY2Mub3Jn; Sean B. Lee, c2xlZTMwQHR1bGFuZS5lZHU=; Anand G. Patel, YW5hbmQucGF0ZWwyQHN0anVkZS5vcmc=
†These authors have contributed equally to this work