Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad de México, México.
Centro de Ciencias de la Complejidad (C3), Universidad Nacional Autónoma de México, Ciudad de México, México.
NPJ Syst Biol Appl. 2024 Sep 2;10(1):99. doi: 10.1038/s41540-024-00422-9.
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.
在包括肝细胞癌在内的几种癌中，已经证明与分化的癌细胞相比，癌症干细胞 (CSC) 具有更强的侵袭性和抗药性。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可能很有价值。基于文献综述，我们构建了一个布尔模型，该模型恢复了对应于衰老、静止、增殖和干细胞样状态下肝细胞和间充质细胞基因表达谱的八个稳定状态（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 的组成性激活增加了增殖干细胞样表型的稳健性。此外，我们发现 p53 失活促进了增殖的肝细胞向间充质干细胞样表型的转变。因此，表型可塑性可能会发生改变，并且在获得突变后，与 CSC 相关的干细胞样表型可能更容易获得。
