Interdisciplinary Programme in Mathematical Sciences, IISc Mathematics Initiative, Indian Institute of Science, Bengaluru, India.
Department of Developmental Biology and Genetics, Indian Institute of Science, Bengaluru, India.
NPJ Syst Biol Appl. 2024 Nov 12;10(1):132. doi: 10.1038/s41540-024-00443-4.
Normal epithelial cells receive proper signals for growth and survival from attachment to the underlying extracellular matrix (ECM). They perceive detachment from the ECM as a stress and die - a phenomenon termed as 'anoikis'. However, metastatic cancer cells acquire anoikis-resistance and circulate through the blood and lymphatics to seed metastasis. Under normal (adherent) growth conditions, the serine-threonine protein kinase Akt stimulates protein synthesis and cell growth, maintaining an anabolic state in the cancer cell. In contrast, previously we showed that the stress due to matrix deprivation is sensed by yet another serine-threonine kinase, AMP-activated protein kinase (AMPK), that inhibits anabolic pathways while promoting catabolic processes. We illustrated a switch from Akt/AMPK in adherent condition to AMPK/Akt in matrix-detached condition, with consequent metabolic switching from an anabolic to a catabolic state, which aids cancer cell stress-survival. In this study, we utilized these experimental data and developed a deterministic ordinary differential equation (ODE)-based mechanistic mathematical model to mimic attachment-detachment signaling network. To do so, we used the framework of insulin-glucagon signaling with consequent metabolic shifts to capture the pathophysiology of matrix-deprived state in breast cancer cells. Using the developed metastatic breast cancer signaling (MBCS) model, we identified perturbation of several signaling proteins such as IRS, PI3K, PKC, GLUT1, IP3, DAG, PKA, cAMP, and PDE3 upon matrix deprivation. Further, in silico molecular perturbations revealed that several feedback/crosstalks like DAG to PKC, PKC to IRS, S6K1 to IRS, cAMP to PKA, and AMPK to Akt are essential for the metabolic switching in matrix-deprived cancer cells. AMPK knockdown simulations identified a crucial role for AMPK in maintaining these adaptive changes. Thus, this mathematical framework provides insights on attachment-detachment signaling with metabolic adaptations that promote cancer metastasis.
正常的上皮细胞通过与基底细胞外基质（ECM）的附着获得生长和存活的适当信号。它们将与 ECM 的分离视为一种应激并死亡——这种现象称为“失巢凋亡”。然而，转移性癌细胞获得了抗失巢凋亡的能力，并通过血液和淋巴循环传播，从而形成转移。在正常（附着）生长条件下，丝氨酸-苏氨酸蛋白激酶 Akt 刺激蛋白质合成和细胞生长，使癌细胞处于合成代谢状态。相比之下，我们之前表明，基质剥夺引起的应激由另一种丝氨酸-苏氨酸激酶 AMP 激活的蛋白激酶（AMPK）感知，AMPK 抑制合成代谢途径，同时促进分解代谢过程。我们说明了从附着状态下的 Akt/AMPK 到基质分离状态下的 AMPK/Akt 的转换，随之而来的代谢从合成代谢向分解代谢的转换，这有助于癌细胞应激存活。在这项研究中，我们利用这些实验数据开发了一个基于确定性常微分方程（ODE）的机制数学模型，以模拟附着-分离信号网络。为此，我们使用胰岛素-胰高血糖素信号的框架，以及随后的代谢转变，来捕捉乳腺癌细胞基质剥夺状态的病理生理学。使用开发的转移性乳腺癌信号（MBCS）模型，我们发现基质剥夺后 IRS、PI3K、PKC、GLUT1、IP3、DAG、PKA、cAMP 和 PDE3 等几种信号蛋白受到干扰。此外，在计算机分子扰动中揭示了 DAG 到 PKC、PKC 到 IRS、S6K1 到 IRS、cAMP 到 PKA 和 AMPK 到 Akt 等几个反馈/串扰对于基质剥夺癌细胞中的代谢转换是必不可少的。AMPK 敲低模拟表明 AMPK 在维持这些适应性变化中起着关键作用。因此，这个数学框架提供了关于附着-分离信号与促进癌症转移的代谢适应的见解。
