Protein-level mutant p53 reporters identify druggable rare precancerous clones in noncancerous tissues
Protein-level mutant p53 reporters identify druggable rare precancerous clones in noncancerous tissues
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DOI：
10.1038/s43018-023-00608-w
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发表时间：
2023-08-03
期刊：
影响因子：
22.7
通讯作者：
Wang，Yuan
中科院分区：
文献类型：
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作者：
Yao，Pengle;Xiao，Peng;Wang，Yuan
检测和靶向非癌组织中的癌前细胞是癌症预防的主要挑战。突变型p53（mutp 53）蛋白质的大量稳定是一种癌症特异性事件，可能标志着癌前细胞，但在体内蛋白质水平的mutp 53报告缺乏。在这里，我们开发了两个转基因蛋白质水平的mutp 53报告，p53 R172 H-Akaluc和p53-mCherry，忠实地模仿mutp 53蛋白在体内的动力学和功能。使用这些报告者，我们在各种癌症模型中鉴定并追踪了深部非癌组织中罕见的癌前克隆。在经典的mutp 53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量变异，上调Ybx 3等癌前阶段特异性基因，并增强氨基酸转运和代谢。在早期而非晚期阶段抑制Ybx 3下游的氨基酸转运蛋白可有效抑制肿瘤发生和肿瘤存活。总之，这些蛋白质水平的mutp 53报告者揭示了早期肿瘤发生过程中癌前细胞的特征和脆弱性，为精确预防癌症铺平了道路。
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 asYbx3and 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.