布尔模型解释了肝癌干细胞出现背后的表型可塑性变化。
A Boolean model explains phenotypic plasticity changes underlying hepatic cancer stem cells emergence.
发表日期：2024 Sep 02
作者：
Alexis Hernández-Magaña, Antonio Bensussen, Juan Carlos Martínez-García, Elena R Álvarez-Buylla
来源：
npj Systems Biology and Applications
摘要：
在包括肝细胞癌在内的多种癌症中，已证明癌症干细胞（CSC）与分化的癌细胞相比具有增强的侵袭性和治疗抵抗力。数学计算工具对于整合实验结果和理解 CSC 出现的表型可塑性机制非常有价值。基于文献综述，我们构建了一个布尔模型，该模型恢复了与衰老、静止、增殖和干细胞样状态下的肝细胞和间充质细胞的基因表达谱相对应的八种稳定状态（吸引子）。分析了与调控网络相关的表观遗传景观。我们观察到 p53、p16、RB 的缺失或 β-catenin 和 YAP1 的组成型激活增加了增殖干细胞样表型的稳健性。此外，我们发现p53失活促进增殖性肝细胞向干细胞样间充质表型的转变。因此，表型可塑性可能会改变，并且在突变获得后可能更容易获得与 CSC 相关的茎样表型。© 2024。作者。
In several carcinomas, including hepatocellular carcinoma, it has been demonstrated that cancer stem cells (CSCs) have enhanced invasiveness and therapy resistance compared to differentiated cancer cells. Mathematical-computational tools could be valuable for integrating experimental results and understanding the phenotypic plasticity mechanisms for CSCs emergence. Based on the literature review, we constructed a Boolean model that recovers eight stable states (attractors) corresponding to the gene expression profile of hepatocytes and mesenchymal cells in senescent, quiescent, proliferative, and stem-like states. The epigenetic landscape associated with the regulatory network was analyzed. We observed that the loss of p53, p16, RB, or the constitutive activation of β-catenin and YAP1 increases the robustness of the proliferative stem-like phenotypes. Additionally, we found that p53 inactivation facilitates the transition of proliferative hepatocytes into stem-like mesenchymal phenotype. Thus, phenotypic plasticity may be altered, and stem-like phenotypes related to CSCs may be easier to attain following the mutation acquisition.© 2024. The Author(s).