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Anatomic Origin of Osteochondrogenic Progenitors Impacts Sensitivity to EWS-FLI1-Induced Transformation

1
Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA
2
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA
3
Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan, Ann Arbor, MI 48109, USA
4
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
*
Authors to whom correspondence should be addressed.
Current address: Department of Cell & Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
Cancers 2019, 11(3), 313; https://doi.org/10.3390/cancers11030313
Received: 14 February 2019 / Revised: 28 February 2019 / Accepted: 1 March 2019 / Published: 6 March 2019
(This article belongs to the Special Issue HOX Genes in Cancer)
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Abstract

Ewing sarcomas predominantly arise in pelvic and stylopod bones (i.e., femur and humerus), likely as a consequence of EWS-FLI1 oncogene-induced transformation of mesenchymal stem/progenitor cells (MSCs). MSCs located in the embryonic superficial zone cells (eSZ) of limbs express anatomically distinct posterior Hox genes. Significantly, high expression of posterior HOXD genes, especially HOXD13, is a hallmark of Ewing sarcoma. These data drove our hypothesis that Hox genes in posterior skeleton MSCs contribute to Ewing sarcoma tumorigenesis. We isolated eSZ cells from stylopod and zeugopod (i.e., tibia/fibula, radius/ulna) bones, from wild-type and Hoxd13 mutant embryos, and tested the impact of EWS-FLI1 transduction on cell proliferation, gene expression, and tumorigenicity. Our data demonstrate that both stylopod and zeugopod eSZ cells tolerate EWS-FLI1 but that stylopod eSZ cells are relatively more susceptible, demonstrating changes in proliferation and gene expression consistent with initiation of malignant transformation. Significantly, loss of Hoxd13 had no impact, showing that it is dispensable for the initiation of EWS-FLI1-induced transformation in mouse MSCs. These findings show that MSCs from anatomically distinct sites are differentially susceptible to EWS-FLI1-induced transformation, supporting the premise that the dominant presentation of Ewing sarcoma in pelvic and stylopod bones is attributable to anatomically-defined differences in MSCs. View Full-Text
Keywords: Ewing sarcoma; Hox; cell of origin; mesenchymal progenitor cells; MSCs Ewing sarcoma; Hox; cell of origin; mesenchymal progenitor cells; MSCs
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Pfaltzgraff, E.R.; Apfelbaum, A.; Kassa, A.P.; Song, J.Y.; Jiang, W.; Suhan, T.K.; Wellik, D.M.; Lawlor, E.R. Anatomic Origin of Osteochondrogenic Progenitors Impacts Sensitivity to EWS-FLI1-Induced Transformation. Cancers 2019, 11, 313.

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