Chedere Adithya, Hari Kishore, Kumar Saurav, Rangarajan Annapoorni, Jolly Mohit Kumar
Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore 560012, India.
Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India.
J Clin Med. 2021 Jan 26;10(3):472. doi: 10.3390/jcm10030472.
Adaptation and survival of cancer cells to various stress and growth factor conditions is crucial for successful metastasis. A double-negative feedback loop between two serine/threonine kinases AMPK (AMP-activated protein kinase) and Akt can regulate the adaptation of breast cancer cells to matrix-deprivation stress. This feedback loop can significantly generate two phenotypes or cell states: matrix detachment-triggered pAMPK/ pAkt state, and matrix (re)attachment-triggered pAkt/ pAMPK state. However, whether these two cell states can exhibit phenotypic plasticity and heterogeneity in a given cell population, i.e., whether they can co-exist and undergo spontaneous switching to generate the other subpopulation, remains unclear. Here, we develop a mechanism-based mathematical model that captures the set of experimentally reported interactions among AMPK and Akt. Our simulations suggest that the AMPK-Akt feedback loop can give rise to two co-existing phenotypes (pAkt/ pAMPK and pAMPK/pAkt) in specific parameter regimes. Next, to test the model predictions, we segregated these two subpopulations in MDA-MB-231 cells and observed that each of them was capable of switching to another in adherent conditions. Finally, the predicted trends are supported by clinical data analysis of The Cancer Genome Atlas (TCGA) breast cancer and pan-cancer cohorts that revealed negatively correlated pAMPK and pAkt protein levels. Overall, our integrated computational-experimental approach unravels that AMPK-Akt feedback loop can generate multi-stability and drive phenotypic switching and heterogeneity in a cancer cell population.
癌细胞对各种应激和生长因子条件的适应与存活对于成功转移至关重要。两种丝氨酸/苏氨酸激酶——AMPK（AMP激活的蛋白激酶）和Akt之间的双负反馈回路可调节乳腺癌细胞对基质剥夺应激的适应。这种反馈回路可显著产生两种表型或细胞状态：基质脱离触发的pAMPK/pAkt状态，以及基质（重新）附着触发的pAkt/pAMPK状态。然而，这两种细胞状态在给定细胞群体中是否能表现出表型可塑性和异质性，即它们是否能共存并自发切换以产生另一个亚群，仍不清楚。在这里，我们建立了一个基于机制的数学模型，该模型捕捉了实验报道的AMPK和Akt之间的相互作用集。我们的模拟表明，在特定参数范围内，AMPK-Akt反馈回路可产生两种共存的表型（pAkt/pAMPK和pAMPK/pAkt）。接下来，为了测试模型预测，我们在MDA-MB-231细胞中分离出这两个亚群，并观察到它们在贴壁条件下均能够转换为另一种状态。最后，癌症基因组图谱（TCGA）乳腺癌和泛癌队列的临床数据分析支持了预测趋势，该分析揭示了pAMPK和pAkt蛋白水平呈负相关。总体而言，我们的综合计算-实验方法揭示了AMPK-Akt反馈回路可产生多稳定性，并驱动癌细胞群体中的表型转换和异质性。
