Schoultz Elin, Liang Shawn, Carlsson Therese, Filges Stefan, Ståhlberg Anders, Fagman Henrik, Wiel Clotilde, Sayin Volkan, Nilsson Mikael
Sahlgrenska Center for Cancer Research, University of Gothenburg, Göteborg, Sweden.
Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
iScience. 2023 Jun 8;26(7):107071. doi: 10.1016/j.isci.2023.107071. eCollection 2023 Jul 21.
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 mutation in mice heterozygous for . In absence of tamoxifen, non-induced mutants developed multiple full-blown lung adenocarcinomas with a latency of 1-3 months whereas thyroid tumors were rare and constrained, although minute 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 BRAF-induced tumorigenesis obey organ-specific traits that might be differentially modified by a shared lineage factor.
癌症的起源细胞决定肿瘤表型，但在具有相似发育特征的器官中，谱系定义转录因子是否会影响肿瘤发生的组织特异性尚不清楚。我们在此证明，在杂合子小鼠中，通过突变靶向肺和甲状腺时，肿瘤的发生和进展明显不同。在没有他莫昔芬的情况下，未诱导的突变体在1-3个月的潜伏期内发展出多个成熟的肺腺癌，而甲状腺肿瘤很少且受到限制，尽管通过变异等位基因测序记录的微小激活在两个组织中相似。诱导的癌基因激活仅在肺中加速肿瘤生长。相比之下，NKX2-1祖细胞在肺和甲状腺发育过程中对突变型Braf的组成型表达同样有反应。在肿瘤早期，肺和甲状腺细胞均短暂下调NKX2-1。这些结果表明，BRAF诱导的肿瘤发生遵循器官特异性特征，这些特征可能会被共同的谱系因子进行不同程度的修饰。
