KBI Biopharma, Durham, NC, USA.
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
Sci Rep. 2022 Jan 18;12(1):883. doi: 10.1038/s41598-022-04878-9.
Cancer cells frequently co-opt molecular programs that are normally activated in specific contexts, such as embryonic development and the response to injury. Determining the impact of cancer-associated mutations on cellular phenotypes within these discrete contexts can provide new insight into how such mutations lead to dysregulated cell behaviors and subsequent cancer onset. Here we assess the impact of heritable BRCA2 mutation on embryonic development and the injury response using a zebrafish model (Danio rerio). Unlike most mouse models for BRCA2 mutation, brca2-mutant zebrafish are fully viable and thus provide a unique tool for assessing both embryonic and adult phenotypes. We find that maternally provided brca2 is critical for normal oocyte development and embryonic survival in zebrafish, suggesting that embryonic lethality associated with BRCA2 mutation is likely to reflect defects in both meiotic and embryonic developmental programs. On the other hand, we find that adult brca2-mutant zebrafish exhibit aberrant proliferation of several cell types under basal conditions and in response to injury in tissues at high risk for cancer development. These divergent effects exemplify the often-paradoxical outcomes that occur in embryos (embryonic lethality) versus adult animals (cancer predisposition) with mutations in cancer susceptibility genes such as BRCA2. The altered cell behaviors identified in brca2-mutant embryonic and adult tissues, particularly in adult tissues at high risk for cancer, indicate that the effects of BRCA2 mutation on cellular phenotypes are both context- and tissue-dependent.
癌细胞经常会篡夺正常情况下在特定环境中激活的分子程序，例如胚胎发育和对损伤的反应。确定与癌症相关的突变对这些离散环境中细胞表型的影响，可以深入了解这些突变如何导致失调的细胞行为以及随后的癌症发生。在这里，我们使用斑马鱼模型（Danio rerio）评估遗传性 BRCA2 突变对胚胎发育和损伤反应的影响。与大多数用于 BRCA2 突变的小鼠模型不同，brca2 突变的斑马鱼是完全存活的，因此为评估胚胎和成年表型提供了独特的工具。我们发现，母源提供的 brca2 对于斑马鱼正常卵母细胞发育和胚胎存活至关重要，这表明与 BRCA2 突变相关的胚胎致死性可能反映了减数分裂和胚胎发育程序的缺陷。另一方面，我们发现成年 brca2 突变的斑马鱼在基础条件下以及在癌症发生风险高的组织中受到损伤时，几种细胞类型表现出异常增殖。这些截然不同的影响体现了在具有癌症易感性基因（如 BRCA2）突变的胚胎（胚胎致死）与成年动物（癌症易感性）中经常出现的矛盾结果。在 brca2 突变的胚胎和成年组织中发现的改变的细胞行为，特别是在癌症发生风险高的成年组织中，表明 BRCA2 突变对细胞表型的影响既与环境有关，也与组织有关。
