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Review
. 2021 Nov 15;13(11):12181-12194.
eCollection 2021.

Challenges in modeling EWS-FLI1-driven transgenic mouse model for Ewing sarcoma

Balaji Ramachandran  1 , Thangarajan Rajkumar  1 , Gopal Gopisetty  1
Affiliations
Review

Challenges in modeling EWS-FLI1-driven transgenic mouse model for Ewing sarcoma

Balaji Ramachandran et al. Am J Transl Res. .

Abstract

EWS-FLI1 is a master regulator of Ewing sarcoma (ES) oncogenesis. Although EWS-FLI1 represents a clear therapeutic target, targeted therapeutic inhibitors are lacking. Scientific literature has indicated accumulating information pertaining to EWS-FLI1 translocation, pathogenesis, function, oncogenic partnerships, and potential clinical relevance. However, attempts to develop EWS-FLI1-driven human-like ES mouse models or in vivo systems ended up with limited success. Establishing such models as preclinical screening tools may accelerate the development of EWS-FLI1 targeted therapeutic inhibitors. This review summarizes the current scenario, which focuses on the limitations, challenges, and possible reasons for past failures in model development and also plausible interim alternatives.

Keywords: EWS-FLI1; Ewing sarcoma; fusion protein; mouse models; progenitor cells; tumor cell of origin.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Scheme of EWS-FLI1-deregulated downstream transcription factors and signaling pathways in progenitor cells. Ectopic expression of EWS-FLI1 oncogenic fusion protein deregulated several downstream transcription factors and signaling pathways leading to ES oncogenesis in MSC, OCPC, and NCC progenitor cells. Such oncogenic changes resulted in a characteristic morphological transformation of mesenchymal spindle shape cells to small round-to-polygonal tumor cells.
Figure 2
Figure 2
Survival outcomes due to EWS-FLI1 expression in progenitor cells, unrelated cell lines, and EWS-FLI1-driven ES mouse model. Deliberate expression of EWS-FLI1 in mouse models as well as in unrelated cell lines (e.g., cardiac myocytes, human fibroblasts, and mouse embryonic fibroblasts) cannot yield a functional model due to EWS-FLI1 toxicity per se. An allograft/xenograft model with progenitors representing presumed COO for ES (e.g., OCPC, NCC, and MSC) would be a viable option owing to their receptivity to EWS-FLI1 expression and better survival without immediate lethality.
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References

    1. Glass AG, Fraumeni JF. Epidemiology of bone cancer in children. J Natl Cancer Inst. 1970;44:187–199. - PubMed
    1. Ries LG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR, editors. Cancer incidence and survival among children and adolescents: United States SEER program 1975-1995. National Cancer Institute, SEER Program. 1999
    1. Wang CC, Schulz MD. Ewing’s sarcoma: a study of fifty cases treated at the Massachusetts General Hospital, 1930-1952 inclusive. N Engl J Med. 1953;248:571–576. - PubMed
    1. Dahlin DC, Coventry MB, Scanlon PW. Ewing’s sarcoma: a critical analysis of 165 cases. J Bone Joint Surg Am. 1961;43-A:185–192. - PubMed
    1. Schleiermacher G, Peter M, Oberlin O, Philip T, Rubie H, Mechinaud F, Sommelet-Olive D, Landman-Parker J, Bours D, Michon J, Delattre O. Increased risk of systemic relapses associated with bone marrow micrometastasis and circulating tumor cells in localized ewing tumor. J. Clin. Oncol. 2003;21:85–91. - PubMed

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