Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Sci Rep. 2018 Jun 20;8(1):9388. doi: 10.1038/s41598-018-27266-8.
Cell-to-cell differences in protein expression in normal tissues and tumors are a common phenomenon, but the underlying principles that govern this heterogeneity are largely unknown. Here, we show that in monolayer cancer cell-line cultures, the expression of the five metabolic enzymes of serine-glycine synthesis (SGS), including its rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), displays stochastic cell-to-cell variation. By contrast, in cancer cell line-derived three-dimensional (3D) microtumors PHGDH expression is restricted to the outermost part of the microtumors' outer proliferative cell layer, while the four other SGS enzymes display near uniform expression throughout the microtumor. A mathematical model suggests that metabolic stress in the microtumor core activates factors that restrict PHGDH expression. Thus, intracellular enzyme expression in growing cell ecosystems can shift to spatially ordered patterns in 3D structured environments due to emergent cell-cell communication, with potential implications for the design of effective anti-metabolic cancer therapies.
正常组织和肿瘤中细胞间蛋白质表达的差异是一种常见现象，但控制这种异质性的基本原理在很大程度上尚不清楚。在这里，我们表明，在单层癌细胞系培养物中，丝氨酸-甘氨酸合成的五种代谢酶（包括其限速酶磷酸甘油酸脱氢酶（PHGDH））的表达表现出随机的细胞间变异性。相比之下，在源自癌细胞系的三维（3D）微肿瘤中，PHGDH 表达仅限于微肿瘤外增殖细胞层的最外层，而其他四个 SGS 酶在整个微肿瘤中几乎均匀表达。一个数学模型表明，微肿瘤核心中的代谢应激会激活限制 PHGDH 表达的因素。因此，由于新兴的细胞间通讯，生长中的细胞生态系统中的细胞内酶表达可以转变为空间有序的模式，这可能对设计有效的抗代谢癌症疗法具有重要意义。
