Adebayo Adedeji K, Bhat-Nakshatri Poornima, Davis Christopher, Angus Steven P, Erdogan Cihat, Gao Hongyu, Green Nick, Kumar Brijesh, Liu Yunlong, Nakshatri Harikrishna
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
iScience. 2024 May 21;27(6):110068. doi: 10.1016/j.isci.2024.110068. eCollection 2024 Jun 21.
Most cells in solid tumors are exposed to oxygen levels between 0.5% and 5%. We developed an approach that allows collection, processing, and evaluation of cancer and non-cancer cells under physioxia, while preventing exposure to ambient air. This aided comparison of baseline and drug-induced changes in signaling pathways under physioxia and ambient oxygen. Using tumor cells from transgenic models of breast cancer and cells from breast tissues of clinically breast cancer-free women, we demonstrate oxygen-dependent differences in cell preference for epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor beta (PDGFRβ) signaling. Physioxia caused PDGFRβ-mediated activation of AKT and extracellular regulated kinase (ERK) that reduced sensitivity to EGFR and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) inhibition and maintained PDGFRβ+ epithelial-mesenchymal hybrid cells with potential cancer stem cell (CSC) properties. Cells in ambient air displayed differential EGFR activation and were more sensitive to targeted therapies. Our data emphasize the importance of oxygen considerations in preclinical cancer research to identify effective drug targets and develop combination therapy regimens.
实体瘤中的大多数细胞暴露于0.5%至5%的氧水平。我们开发了一种方法，可在模拟生理氧环境下收集、处理和评估癌细胞与非癌细胞，同时防止暴露于环境空气中。这有助于比较模拟生理氧环境和环境氧条件下信号通路的基线变化和药物诱导变化。利用来自乳腺癌转基因模型的肿瘤细胞以及临床无乳腺癌女性乳腺组织的细胞，我们证明了细胞对表皮生长因子受体（EGFR）或血小板衍生生长因子受体β（PDGFRβ）信号传导的偏好存在氧依赖性差异。模拟生理氧环境导致PDGFRβ介导的AKT和细胞外调节激酶（ERK）激活，降低了对EGFR和磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α（PIK3CA）抑制的敏感性，并维持了具有潜在癌症干细胞（CSC）特性的PDGFRβ+上皮-间质杂交细胞。环境空气中的细胞表现出不同的EGFR激活，并且对靶向治疗更敏感。我们的数据强调了在临床前癌症研究中考虑氧因素对于确定有效药物靶点和制定联合治疗方案的重要性。
