Tumour progression relies on interactions with untransformed cells in the tumour microenvironment (TME), including cancer-associated fibroblasts (CAFs), which promote blood supply, tumour progression, and immune evasion. Eph receptor tyrosine kinases are cell guidance receptors that are most active during development but re-emerge in cancer and are recognised drug targets. EphA3 is overexpressed in a wide range of tumour types, and we previously found expression particularly in stromal and vascular tissues of the TME. To investigate its role in the TME, we generated transgenic mice with inducible shRNA-mediated knockdown of EphA3 expression. EphA3 knockdown was confirmed in aortic mesenchymal stem cells (MSCs), which displayed reduced angiogenic capacity. In mice with syngeneic lung tumours, EphA3 knockdown reduced vasculature and CAF/MSC-like cells in tumours, and inhibited tumour growth, which was confirmed also in a melanoma model. Single cell RNA sequencing analysis of multiple human tumour types confirmed EphA3 expression in CAFs, including in breast cancer, where EphA3 was particularly prominent in perivascular- and myofibroblast-like CAFs. Our results thus indicate expression of the cell guidance receptor EphA3 in distinct CAF subpopulations is important in supporting tumour angiogenesis and tumour growth, highlighting its potential as a therapeutic target.
肿瘤进展依赖于与肿瘤微环境（TME）中未转化细胞的相互作用，包括癌症相关成纤维细胞（CAFs），这些细胞促进血液供应、肿瘤进展和免疫逃逸。Eph受体酪氨酸激酶是细胞导向受体，在发育过程中最为活跃，但在癌症中重新出现，并被公认为药物靶点。EphA3在多种肿瘤类型中过度表达，我们先前发现其在TME的基质和血管组织中尤为显著。为探究其在TME中的作用，我们构建了可诱导shRNA介导的EphA3表达敲低的转基因小鼠。在主动脉间充质干细胞（MSCs）中确认了EphA3敲低，这些细胞显示出血管生成能力降低。在同基因肺肿瘤小鼠中，EphA3敲低减少了肿瘤中的血管系统和CAF/MSC样细胞，并抑制了肿瘤生长，这在黑色素瘤模型中也得到证实。对多种人类肿瘤类型的单细胞RNA测序分析证实了EphA3在CAFs中的表达，包括在乳腺癌中，EphA3在血管周围样和肌成纤维细胞样CAFs中尤为突出。因此，我们的研究结果表明，细胞导向受体EphA3在特定CAF亚群中的表达对支持肿瘤血管生成和肿瘤生长至关重要，突显了其作为治疗靶点的潜力。
Inhibition of EphA3 Expression in Tumour Stromal Cells Suppresses Tumour Growth and Progression
肿瘤(癌症)患者之家