通过共享的谱系因子，定向肺和甲状腺的致癌性BRAF的组织特异性。
Tissue specificity of oncogenic BRAF targeted to lung and thyroid through a shared lineage factor.
发表日期：2023 Jul 21
作者：
Elin Schoultz, Shawn Liang, Therese Carlsson, Stefan Filges, Anders Ståhlberg, Henrik Fagman, Clotilde Wiel, Volkan Sayin, Mikael Nilsson
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
癌症的起始细胞决定了肿瘤的表型，但是否存在能影响具有相似发育特征的器官中肿瘤发生组织特异性的定义系转录因子，目前尚不清楚。本研究在在Nkx2.1CreERT2鼠标中靶向Braf突变的肺和甲状腺中展示了肿瘤的发展和进展显著不同，这些鼠标是NKX2-1异型子与Nkx2-1杂合子。在没有使用他莫昔芬的情况下，非感应的Nkx2.1CreERT2；BrafCA/+突变体发展出多个完全发展的肺腺癌，并且潜伏期为1-3个月，而甲状腺肿瘤比较罕见且受限制，尽管两种组织中都存在相似的BrafCA活化，通过变异等位基因测序得到了证实。诱导的癌基因活化只在肺部加速肿瘤生长。相比之下，NKX2-1正向祖细胞对于在肺和甲状腺发育期间表达突变Braf都有相同的反应。在早期肿瘤阶段，肺和甲状腺细胞都短暂地下调了NKX2-1的表达。这些结果表明，BRAFV600E诱导的肿瘤发生服从于器官特异性特征，并且这些特征可能会被共享的谱系因子不同地调整。© 2023作者。
Cells of origin in cancer determine tumor phenotypes, but whether lineage-defining transcription factors might influence tissue specificity of tumorigenesis among organs with similar developmental traits are unknown. We demonstrate here that tumor development and progression markedly differ in lung and thyroid targeted by Braf mutation in Nkx2.1CreERT2 mice heterozygous for Nkx2-1. In absence of tamoxifen, non-induced Nkx2.1CreERT2;BrafCA/+ mutants developed multiple full-blown lung adenocarcinomas with a latency of 1-3 months whereas thyroid tumors were rare and constrained, although minute BrafCA activation documented by variant allele sequencing was similar in both tissues. Induced oncogene activation accelerated neoplastic growth only in the lungs. By contrast, NKX2-1+ progenitor cells were equally responsive to constitutive expression of mutant Braf during lung and thyroid development. Both lung and thyroid cells transiently downregulated NKX2-1 in early tumor stages. These results indicate that BRAFV600E-induced tumorigenesis obey organ-specific traits that might be differentially modified by a shared lineage factor.© 2023 The Author(s).