Mechanical Engineering Department, School of Engineering and Architecture, University of Zaragoza, C/ Maria de Luna, Zaragoza, 50018, Spain; Engineering Research Institute of Aragón (I3A), University of Zaragoza, C/ Mariano Esquillor, Zaragoza, 50018, Spain.
Engineering Research Institute of Aragón (I3A), University of Zaragoza, C/ Mariano Esquillor, Zaragoza, 50018, Spain; Aragón Health Research Institute (IISAragón), Avda. San Juan Bosco, Zaragoza, 50009, Spain.
Comput Biol Med. 2023 Sep;164:107291. doi: 10.1016/j.compbiomed.2023.107291. Epub 2023 Aug 1.
Cellular adaptation is the ability of cells to change in response to different stimuli and environmental conditions. It occurs via phenotypic plasticity, that is, changes in gene expression derived from changes in the physiological environment. This phenomenon is important in many biological processes, in particular in cancer evolution and its treatment. Therefore, it is crucial to understand the mechanisms behind it. Specifically, the emergence of the cancer stem cell phenotype, showing enhanced proliferation and invasion rates, is an essential process in tumour progression. We present a mathematical framework to simulate phenotypic heterogeneity in different cell populations as a result of their interaction with chemical species in their microenvironment, through a continuum model using the well-known concept of internal variables to model cell phenotype. The resulting model, derived from conservation laws, incorporates the relationship between the phenotype and the history of the stimuli to which cells have been subjected, together with the inheritance of that phenotype. To illustrate the model capabilities, it is particularised for glioblastoma adaptation to hypoxia. A parametric analysis is carried out to investigate the impact of each model parameter regulating cellular adaptation, showing that it permits reproducing different trends reported in the scientific literature. The framework can be easily adapted to any particular problem of cell plasticity, with the main limitation of having enough cells to allow working with continuum variables. With appropriate calibration and validation, it could be useful for exploring the underlying processes of cellular adaptation, as well as for proposing favourable/unfavourable conditions or treatments.
细胞适应是细胞响应不同刺激和环境条件而改变的能力。它通过表型可塑性发生，即源自生理环境变化的基因表达变化。这种现象在许多生物学过程中很重要，特别是在癌症进化及其治疗中。因此，了解其背后的机制至关重要。具体来说，癌症干细胞表型的出现，表现为增殖和侵袭率的提高，是肿瘤进展中的一个重要过程。我们提出了一个数学框架，通过使用著名的内部变量概念来模拟不同细胞群体由于与微环境中化学物质相互作用而产生的表型异质性，通过连续体模型来模拟细胞表型。该模型源自守恒定律，将细胞所经历的刺激的历史与细胞表型之间的关系以及该表型的遗传结合在一起。为了说明模型的能力，我们将其特别应用于脑胶质瘤对缺氧的适应。进行了参数分析以研究调节细胞适应的每个模型参数的影响，结果表明，它可以再现科学文献中报道的不同趋势。该框架可以轻松适应任何特定的细胞可塑性问题，主要限制是要有足够的细胞来允许使用连续体变量。经过适当的校准和验证，它可以用于探索细胞适应的潜在过程，以及提出有利/不利的条件或治疗方法。
