Department of Pediatrics, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA, 48109.
Department of Pediatrics, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 15224.
Neoplasia. 2019 Oct;21(10):1063-1072. doi: 10.1016/j.neo.2019.08.007. Epub 2019 Sep 13.
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.
尤因肉瘤是一种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率令人沮丧，因此迫切需要更好地了解这种疾病特有的细胞转移机制。我们最近的工作表明，微环境应激通过激活Src 导致尤因肉瘤细胞侵袭增加。此外，我们还表明细胞外基质蛋白 tenascin C（TNC）促进尤因肉瘤的转移。TNC 和 Src 的主要作用是介导细胞-细胞和细胞-基质相互作用，导致细胞迁移、侵袭和黏附的变化。然而，TNC 和 Src 在这些过程中是如何联系的，仍然很大程度上未知。我们假设 TNC 通过激活 Src 成为尤因肉瘤侵袭小体形成的正调节剂。我们在这里证明，肿瘤细胞内源性和外源性的 TNC 都可以增强尤因肉瘤中的 Src 激活和侵袭小体形成。我们发现，微环境应激上调 TNC 的表达，而应用Src 抑制剂 dasatinib 则可以抑制这种表达，这表明 TNC 的表达和 Src 的激活合作促进了侵袭表型。这项工作报告了应激诱导的 TNC 表达对增强细胞侵袭小体形成的影响，为 TNC 和 Src 之间的正反馈环提供了证据，以促进细胞转移行为，并强调了一种通过微环境驱动的 TNC 表达可以在尤因肉瘤中进行治疗靶向的途径。
