Intratumoral heterogeneity is a major ongoing challenge in the effective therapeutic targeting of cancer. Accumulating evidence suggests that a fraction of cells within a tumor termed Cancer Stem Cells (CSCs) are primarily responsible for this diversity resulting in therapeutic resistance and metastasis. Adding to this complexity, recent studies have shown that there can be different subpopulations of CSCs with varying biochemical and biophysical traits resulting in varied dissemination and drug-resistance potential. Moreover, cancer cells can exhibit a high level of plasticity or the ability to dynamically switch between CSC and non-CSC states or among different subsets of CSCs. In addition, CSCs also display extensive metabolic plasticity. The molecular mechanisms underlying these different interconnected axes of plasticity has been under extensive investigation and the trans-differentiation process of Epithelial to Mesenchymal transition (EMT) has been identified as a major contributing factor. Besides genetic and epigenetic factors, CSC plasticity is also shaped by non-cell-autonomous effects such as the tumor microenvironment (TME). In this review, we discuss the latest developments in decoding mechanisms and implications of CSC plasticity in tumor progression at biochemical and biophysical levels, and the latest in silico approaches being taken for characterizing cancer cell plasticity. These efforts can help improve existing therapeutic approaches by taking into consideration the contribution of cellular plasticity/heterogeneity in enabling drug resistance.

中文翻译：

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癌症干细胞可塑性——致命的交易。


肿瘤内异质性是癌症有效治疗靶向的主要持续挑战。越来越多的证据表明，肿瘤内称为癌症干细胞（CSC）的一小部分细胞是造成这种多样性并导致治疗耐药和转移的主要原因。最近的研究表明，不同的 CSC 亚群具有不同的生化和生物物理特征，从而导致不同的传播和耐药潜力，这加剧了这种复杂性。此外，癌细胞可以表现出高水平的可塑性或在CSC和非CSC状态之间或在CSC的不同亚群之间动态切换的能力。此外，CSC 还表现出广泛的代谢可塑性。这些不同的相互关联的可塑性轴背后的分子机制已得到广泛研究，上皮向间质转化（EMT）的转分化过程已被确定为主要影响因素。除了遗传和表观遗传因素外，CSC 的可塑性还受到肿瘤微环境 (TME) 等非细胞自主效应的影响。在这篇综述中，我们讨论了解码机制的最新进展以及CSC可塑性在生化和生物物理水平上对肿瘤进展的影响，以及用于表征癌细胞可塑性的最新计算机方法。这些努力可以通过考虑细胞可塑性/异质性在实现耐药性方面的贡献来帮助改进现有的治疗方法。