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EPHA2 Receptor Signaling in Breast Cancer Mechanotransduction

乳腺癌机械转导中的 EPHA2 受体信号转导

基本信息

批准号：
10609917
负责人：
ELENA B PASQUALE
金额：
$ 52.05万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609917
关键词：
Affect Binding Biochemical Biological Assay Breast Cancer Cell Breast Cancer Model CSNK1A1 gene Cell Surface Receptors Cell membrane Consensus Cues Cyclic AMP-Dependent Protein Kinases EPHA2 gene EphA2 Receptor Ephrins Epithelium Extracellular Matrix Invaded LYN gene Ligand Binding Ligand Binding Domain Ligands Malignant Neoplasms Mammary Neoplasms Mechanics Mesenchymal Molecular Mus Neoplasm Metastasis Nuclear Organoids Pathway interactions Peptides Phosphorylation Phosphorylation Inhibition Phosphorylation Site Phosphotransferases Play Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Receptor Signaling Research Role Serine Serine/Threonine Phosphorylation Signal Induction Signal Pathway Signal Transduction TWIST1 gene Threonine Phosphorylation Site Tumor Cell Invasion Tumor Promotion Tyrosine Tyrosine Phosphorylation Site Work Xenograft Model breast cancer progression cancer cell cancer invasiveness extracellular in vivo malignant breast neoplasm mammary epithelium mechanical force mechanical signal mechanotransduction neoplastic cell novel strategies recruit response src-Family Kinases three dimensional cell culture transcription factor tumor tumor microenvironment tumor progression

项目摘要

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.

总结肿瘤微环境中刚性细胞外基质（ECM）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EPHA 2非典型的关键作用信号转导在促进上皮-间质转化（EMT）和肿瘤侵袭转移中的作用增加肿瘤微环境中ECM的硬度。此外，我们发现，激活EPHA 2 ephrinA 1配体的典型信号传导有效抑制僵硬诱导的乳腺癌细胞侵袭。基于这些结果，我们假设EPHA 2作为一个关键变阻器，来自肿瘤微环境的机械和生物化学线索来调节乳腺中的机械信号传导癌症进展和转移。我们建议将生物化学、2D和3D细胞培养测定相结合，体内异种移植模型，以阐明EPHA 2信号传导机制在乳腺癌恶性肿瘤诱导通过三个具体目标实现ECM刚性。(1)确定ECM刚性如何激活EPHA 2非典型信号传导促进EMT和侵袭。(2)确定EPHA 2规范信号传导如何阻断EMT， ECM刚性诱导的侵袭。(3)检查EPHA 2非经典和经典信号传导在乳腺癌在体内的侵袭和转移。总之，这些研究将为潜在的有用性提供信息，激活EphA 2经典信号传导以抑制乳腺癌侵袭和转移。