文章：

蛋白水平突变p53报告者在非癌组织中发现可药物治疗的罕见癌前克隆

Protein-level mutant p53 reporters identify druggable rare precancerous clones in noncancerous tissues 

原文发布日期：2023-08-03 

英文摘要：

Detecting and targeting precancerous cells in noncancerous tissues is a major challenge for cancer prevention. Massive stabilization of mutant p53 (mutp53) proteins is a cancer-specific event that could potentially mark precancerous cells, yet in vivo protein-level mutp53 reporters are lacking. Here we developed two transgenic protein-level mutp53 reporters, p53R172H–Akaluc and p53–mCherry, that faithfully mimic the dynamics and function of mutp53 proteins in vivo. Using these reporters, we identified and traced rare precancerous clones in deep noncancerous tissues in various cancer models. In classic mutp53-driven thymic lymphoma models, we found that precancerous clones exhibit broad chromosome number variations, upregulate precancerous stage-specific genes such as Ybx3 and enhance amino acid transport and metabolism. Inhibiting amino acid transporters downstream of Ybx3 at the early but not late stage effectively suppresses tumorigenesis and prolongs survival. Together, these protein-level mutp53 reporters reveal undercharacterized features and vulnerabilities of precancerous cells during early tumorigenesis, paving the way for precision cancer prevention. 

摘要翻译：

在非癌组织中检测和靶向前癌细胞是非癌症预防的主要挑战。突变性p53蛋白（mutp53）蛋白质的大量稳定化是一种癌症特定事件，可能标记前癌细胞，但在体外蛋白水平上的mutp53报告系统目前缺乏。我们开发了两种转基因蛋白级mutp53报告系统，分别为p53R172H–Akaluc和p53–mCherry，它们能够忠实模拟活体中mutp53蛋白的动力学和功能。利用这些报告系统，我们在各种癌症模型中识别并追踪了深部非癌组织中的稀有前癌细胞群。在经典的mutp53驱动的胸腺淋巴瘤模型中，我们发现前癌细胞群表现出广泛的染色体数变化，并上调了阶段特定的前癌细胞基因如Ybx3，同时增强氨基酸转运和代谢功能。通过抑制Ybx3下游氨基酸转运器在早期但非晚期作用，能够有效抑制肿瘤生长并延长生存期。综合来看，这些蛋白级mutp53报告系统揭示了前癌细胞在早期肿瘤发生过程中尚未被充分-characterized的特征和易受攻击性，为精准预防癌症奠定了基础。 

原文链接：

https://www.nature.com/articles/s43018-023-00608-w