EPHA2 Receptor Signaling in Breast Cancer Mechanotransduction

摘要 刚性细胞外基质(ECM)在肿瘤微环境中产生的机械力起着关键作用 在肿瘤进展和转移中的作用。我们最近发现了EphA2的一个关键作用 促进上皮-间充质转化(EMT)和肿瘤侵袭转移的信号反应 增加肿瘤微环境中细胞外基质的硬度。此外，我们还发现EphA2的激活 典型的信号通过ewitinA1配体有效地抑制僵硬诱导的乳腺癌细胞侵袭性。 基于这些结果，我们假设EphA2作为一个关键的变阻器发挥作用，将两者整合在一起 来自肿瘤微环境的机械和生化信号调节乳腺中的机械信号 癌症的进展和转移。我们建议将生化、2D和3D细胞培养分析结合起来，并 在体异种移植模型研究EphA2信号转导机制 ECM通过三个具体目标实现刚性。(1)确定ECM刚性如何激活EphA2非规范 发出促进EMT和侵袭的信号。(2)确定EphA2规范信号如何阻止EMT和 ECM僵硬引起的侵袭。(3)研究EphA2非正则信号和正则信号在细胞周期中的作用 乳腺癌在体内的侵袭和转移。总而言之，这些研究将揭示潜在的有用之处 激活EphA2规范信号以抑制乳腺癌侵袭和转移。

SUMMARY Mechanical forces generated by a rigid extracellular matrix (ECM) in the tumor microenvironment play a key role in tumor progression and metastasis. We recently discovered a critical role of EPHA2 non-canonical signaling in promoting epithelial-mesenchymal transition (EMT) and tumor invasion and metastasis in response to increasing ECM stiffness in the tumor microenvironment. Furthermore, we found that activation of EPHA2 canonical signaling by the ephrinA1 ligand potently inhibits stiffness-induced breast cancer cell invasiveness. Based on these results, we hypothesize that EPHA2 functions as a key rheostat that integrates both mechanical and biochemical cues from the tumor microenvironment to regulate mechanosignaling in breast cancer progression and metastasis. We propose to combine biochemical, 2D and 3D cell culture assays, and in vivo xenograft models to elucidate EPHA2 signaling mechanisms in breast cancer malignancy induced by ECM rigidity through three specific aims. (1) Determine how ECM rigidity activates EPHA2 non-canonical signaling to promote EMT and invasion. (2) Determine how EPHA2 canonical signaling blocks EMT and invasion induced by ECM rigidity. (3) Examine the role of EPHA2 non-canonical and canonical signaling in breast cancer invasion and metastasis in vivo. Together, these studies will inform on the potential usefulness of activating EphA2 canonical signaling for inhibition of breast cancer invasiveness and metastasis.