PO.MCB09.01 · 分子与细胞生物学
细胞密度驱动肿瘤微环境中成纤维细胞样细胞的谷氨酰胺合成
Cell density drives glutamine synthesis in fibroblast-like cells in the tumor microenvironment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
致密的纤维组织是乳腺癌风险升高的标志之一，由丰富的细胞外基质（ECM）和塑造肿瘤微环境（TME）的成纤维细胞样细胞组成。这些成纤维细胞样细胞可产生细胞密度不一的区域，进而影响局部营养可用性。在实体瘤中，血管化不良会产生营养剥夺的环境，其中氨基酸尤其是谷氨酰胺成为限制性因素。谷氨酰胺对许多细胞过程至关重要，包括补充 TCA 循环、抗氧化防御、蛋白质合成和核苷酸生成。侵袭性三阴性乳腺癌细胞往往无法利用谷氨酰胺合成酶（GS）自身从头合成谷氨酰胺，而依赖外源来源以实现生长和存活。TME 内的成纤维细胞样细胞可能通过 GS 活性产生并供应谷氨酰胺来进行代偿。尽管这种代谢依赖性已在卵巢癌中得到证实，但 GS 在乳腺 TME 内成纤维细胞样细胞中如何被调控，以及是否受细胞密度影响，仍属未知。我们假设高细胞密度作为一种非细胞自主性的代谢信号，在谷氨酰胺剥夺条件下上调成纤维细胞样细胞中的 GS。为验证这一点，我们将来自乳腺、皮肤和肺组织的成纤维细胞，以及祖成纤维细胞样细胞系（10T1/2 和 MC3T3），在有或无外源谷氨酰胺存在下以不同密度培养。初步数据显示，近乎汇合的成纤维细胞样细胞在谷氨酰胺剥夺情况下仍上调 GS 并维持活跃的蛋白质翻译，提示致密培养物采取了一种赋予其相较于低汇合度细胞更多优势的代谢状态。这些发现指向了一种潜在机制，即乳腺 TME 中的成纤维细胞样细胞促进谷氨酰胺可用性，进而促进肿瘤进展。由于直接抑制 GS 具有神经毒性，鉴定 GS 的上游、密度依赖性调控因子代表了一条有前景的治疗途径，可选择性地破坏对侵袭性乳腺癌的谷氨酰胺供应。
查看英文原文 English abstract
Dense fibrous tissue, a hallmark of increased breast cancer risk, is composed of abundant extracellular matrix (ECM) and fibroblast-like cells that shape the tumor microenvironment (TME). These fibroblast-like cells can create regions of variable cell density, which in turn influences local nutrient availability. In solid tumors, poor vascularization generates a nutrient-deprived environment where amino acids, particularly glutamine, become limiting. Glutamine is essential for many cell processes, including replenishment of the TCA cycle, antioxidant defense, protein synthesis, and nucleotide production. Aggressive triple-negative breast cancer cells are often unable to synthesize their own glutamine de novo using glutamine synthetase (GS) and rely on exogenous sources for growth and survival. Fibroblast-like cells within the TME may compensate by producing and supplying glutamine through GS activity. Although this metabolic dependency has been demonstrated in ovarian cancer, how GS is regulated in fibroblast-like cells within the breast TME, and whether it is influenced by cell density, remains unknown. We hypothesize that high cell density acts as a non-cell-autonomous metabolic cue, upregulating GS in fibroblast-like cells under glutamine-deprived conditions. To test this, fibroblasts from mammary, skin, and lung tissue, as well as progenitor fibroblast-like cell lines (10T1/2 and MC3T3), were cultured at varying densities in the presence or absence of exogenous glutamine. Preliminary data show that near-confluent fibroblast-like cells upregulate GS and maintain active protein translation despite glutamine deprivation, suggesting that dense cultures adopt a metabolic state that gives them an added advantage compared to less-confluent cells. These findings point to a potential mechanism by which fibroblast-like cells in the breast TME promote glutamine availability and, consequently, tumor progression. Because direct GS inhibition is neurotoxic, identifying upstream, density-dependent regulators of GS represents a promising therapeutic avenue for selectively disrupting glutamine supply to aggressive breast cancers.
利益披露 Disclosure
L. Shakachite, None..
N. N. Pavlova, None.