Ewing sarcoma is a bone tumor most commonly diagnosed in adolescents and young adults. Survival for patients with recurrent or metastatic Ewing sarcoma is dismal and there is a dire need to better understand the mechanisms of cell metastasis specific to this disease. Our recent work demonstrated that microenvironmental stress leads to increased Ewing sarcoma cell invasion through Src activation. Additionally, we have shown that the matricellular protein tenascin C (TNC) promotes metastasis in Ewing sarcoma. A major role of both TNC and Src is mediation of cell-cell and cell-matrix interactions resulting in changes in cell motility, invasion, and adhesion. However, it remains largely unknown, if and how, TNC and Src are linked in these processes. We hypothesized that TNC is a positive regulator of invadopodia formation in Ewing sarcoma through its ability to activate Src. We demonstrate here that both tumor cell endogenous and exogenous TNC can enhance Src activation and invadopodia formation in Ewing sarcoma. We found that microenvironmental stress upregulates TNC expression and this is dampened with application of the Src inhibitor dasatinib, suggesting that TNC expression and Src activation cooperate to promote the invasive phenotype. This work reports the impact of stress-induced TNC expression on enhancing cell invadopodia formation, provides evidence for a feed forward loop between TNC and Src to promote cell metastatic behavior, and highlights a pathway by which microenvironment-driven TNC expression could be therapeutically targeted in Ewing sarcoma.

中文翻译：

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微环境因素驱动腱生蛋白C和Src的合作以促进尤文肉瘤的Invadopodia形成。

尤因肉瘤是最常见于青少年和年轻人的骨肿瘤。复发性或转移性尤因肉瘤患者的生存状况令人沮丧，迫切需要更好地了解特定于该疾病的细胞转移机制。我们最近的工作表明，微环境压力通过Src激活导致尤因肉瘤细胞侵袭的增加。此外，我们已经表明，基质细胞蛋白腱糖蛋白C（TNC）促进尤文肉瘤的转移。TNC和Src的主要作用是介导细胞-细胞和细胞-基质相互作用，从而导致细胞运动，侵袭和粘附的改变。但是，在这些过程中，是否以及如何将TNC和Src链接起来，仍然是一个未知数。我们假设TNC通过激活Src的能力而成为尤因肉瘤侵袭性伪足形成的正调节剂。我们在这里证明肿瘤细胞内源性和外源性TNC都可以增强尤因肉瘤中的Src激活和invadopodia的形成。我们发现微环境压力上调了TNC的表达，这被Src抑制剂dasatinib的应用所抑制，这表明TNC的表达和Src的激活共同促进了侵袭性表型。这项工作报告了应激诱导的TNC表达对增强细胞侵袭足形成的影响，为TNC和Src之间的前馈环促进细胞转移行为提供了证据，并着重指出了微环境驱动的TNC表达可通过靶向治疗的途径。尤文氏肉瘤。我们在这里证明肿瘤细胞内源性和外源性TNC都可以增强尤因肉瘤中的Src激活和invadopodia的形成。我们发现微环境压力上调了TNC的表达，这被Src抑制剂dasatinib的应用所抑制，这表明TNC的表达和Src的激活共同促进了侵袭性表型。这项工作报告了应力诱导的TNC表达对增强细胞侵袭足形成的影响，为TNC和Src之间的前馈环促进细胞转移行为提供了证据，并突出了微环境驱动的TNC表达可通过靶向治疗的途径。尤文氏肉瘤。我们在这里证明肿瘤细胞内源性和外源性TNC都可以增强尤因肉瘤中的Src激活和invadopodia的形成。我们发现微环境压力上调了TNC的表达，这被Src抑制剂dasatinib的应用所抑制，这表明TNC的表达和Src的激活共同促进了侵袭性表型。这项工作报告了应激诱导的TNC表达对增强细胞侵袭足形成的影响，为TNC和Src之间的前馈环促进细胞转移行为提供了证据，并着重指出了微环境驱动的TNC表达可通过靶向治疗的途径。尤文氏肉瘤。我们发现微环境压力上调了TNC的表达，这被Src抑制剂dasatinib的应用所抑制，这表明TNC的表达和Src的激活共同促进了侵袭性表型。这项工作报告了应力诱导的TNC表达对增强细胞侵袭足形成的影响，为TNC和Src之间的前馈环促进细胞转移行为提供了证据，并突出了微环境驱动的TNC表达可通过靶向治疗的途径。尤文氏肉瘤。我们发现微环境压力上调了TNC的表达，这被Src抑制剂dasatinib的应用所抑制，这表明TNC的表达和Src的激活共同促进了侵袭性表型。这项工作报告了应激诱导的TNC表达对增强细胞侵袭足形成的影响，为TNC和Src之间的前馈环促进细胞转移行为提供了证据，并着重指出了微环境驱动的TNC表达可通过靶向治疗的途径。尤文氏肉瘤。