癌前细胞在非癌组织中的检测和靶向治疗是癌症预防的一大挑战。突变p53（mutp53）蛋白的大量稳定是一种特异性于癌症的事件，有可能标记癌前细胞，然而缺乏体内蛋白水平的mutp53报告基因。本研究开发了两种转基因蛋白水平的mutp53报告基因，p53R172H-Akaluc和p53-mCherry，能够真实模拟体内mutp53蛋白的动态和功能。利用这些报告基因，在不同的癌症模型中，我们鉴定并追踪到存在于深层非癌组织中的罕见癌前克隆。在传统的mutp53驱动的胸腺淋巴瘤模型中，我们发现癌前克隆表现出广泛的染色体数目变异，上调癌前特异性基因如Ybx3，并增强氨基酸转运和代谢。在Ybx3下游的氨基酸转运体的抑制在早期而不是晚期有效抑制肿瘤发生并延长生存。这些蛋白水平的mutp53报告基因揭示了早期肿瘤发生过程中癌前细胞的未充分研究的特征和易感性，为精确癌症预防铺平了道路。© 2023. This is an author-produced version of a paper subsequently published in Journal of Experimental Medicine. Uploaded in accordance with the publisher's self-archiving policy.

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.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.