标题： 乳腺癌表型异质性的数学模型及其对治疗策略的影响 显示英文标题

标题： A mathematical model for phenotypic heterogeneity in breast cancer with implications for therapeutic strategies

摘要： 不可避免的是，几乎所有癌症患者都会对靶向治疗产生耐药性。 肿瘤内异质性（ITH）是药物耐受的主要原因。 能够定量解释实验的数学模型有助于理解ITH的起源，进而可用于探索有效的治疗方案。 在这里，我们开发了一个数学模型，通过利用HER2+和HER2-细胞可以对称或不对称分裂的观察来研究乳腺癌中的ITH。 我们对细胞比例演化的预测与单细胞实验结果在数量上一致。 值得注意的是，从一个HER2-细胞（或反之）中出现的HER2+细胞的克隆大小，在大约四次细胞倍增后与实验结果完全一致，而无需调整模型中的任何参数。 该理论定量地解释了乳腺癌肿瘤在不同治疗方案下的实验数据。 然后，我们使用该模型预测，不仅两种药物的顺序，而且每种药物的治疗周期和肿瘤细胞的可塑性都可以被操控以提高治疗效果。 当数学模型与患者数据相结合时，可以轻松探索广泛参数范围，这可能有助于设计有效疗法提供见解。 显示英文摘要

摘要： Inevitably, almost all cancer patients develop resistance to targeted therapy. Intratumor heterogeneity (ITH) is a major cause of drug resistance. Mathematical models that explain experiments quantitatively is useful in understanding the origin of ITH, which then could be used to explore scenarios for efficacious therapy. Here, we develop a mathematical model to investigate ITH in breast cancer by exploiting the observation that HER2+ and HER2- cells could divide symmetrically or asymmetrically. Our predictions for the evolution of cell fractions are in quantitative agreement with single-cell experiments. Remarkably, the colony size of HER2+ cells emerging from a single HER2- cell (or vice versa), which occurs in about four cell doublings, agrees perfectly with experimental results, without tweaking any parameter in the model. The theory quantitatively explains experimental data on the responses of breast cancer tumor under different treatment protocols. We then used the model to predict that, not only the order of two drugs, but also the treatment period for each drug and the tumor cell plasticity could be manipulated to improve the treatment efficacy. Mathematical models, when integrated with data on patients, make possible exploration of a broad range of parameters readily, which might provide insights in devising effective therapies.