Intra-tumour phenotypic heterogeneity limits accuracy of clinical diagnostics and hampers the efficiency of anti-cancer therapies. Dealing with this cellular heterogeneity requires adequate understanding of its sources, which is extremely difficult, as phenotypes of tumour cells integrate hardwired (epi)mutational differences with the dynamic responses to microenvironmental cues. The later comes in form of both direct physical interactions, as well as inputs from gradients of secreted signalling molecules. Furthermore, tumour cells can not only receive microenvironmental cues, but also produce them. Despite high biological and clinical importance of understanding spatial aspects of paracrine signaling, adequate research tools are largely lacking. Here, a partial differential equation (PDE)-based mathematical model is developed that mimics the process of cell ablation. This model suggests how each cell might contribute to the microenvironment by either absorbing or secreting diffusible factors, and quantifies the extent to which observed intensities can be explained via diffusion-mediated signalling. The model allows for the separation of phenotypic responses to signalling gradients within tumour microenvironments from the combined influence of responses mediated by direct physical contact and hardwired (epi)genetic differences. The method is applied to a multi-channel immunofluorescence in situ hybridisation (iFISH)-stained breast cancer histological specimen, and correlations are investigated between: HER2 gene amplification, HER2 protein expression and cell interaction with the diffusible microenvironment. This approach allows partial deconvolution of the complex inputs that shape phenotypic heterogeneity of tumour cells and identifies cells that significantly impact gradients of signalling molecules.

中文翻译：

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模拟消融，用于检测在组织学分析中影响旁分泌信号传导的细胞。

肿瘤内表型异质性限制了临床诊断的准确性，并阻碍了抗癌治疗的效率。处理这种细胞异质性需要充分了解其来源，这非常困难，因为肿瘤细胞的表型将硬连线（epi）突变差异与对微环境线索的动态响应整合在一起。后者以直接的物理相互作用以及来自分泌的信号分子梯度的输入的形式出现。此外，肿瘤细胞不仅可以接受微环境提示，还可以产生它们。尽管了解旁分泌信号的空间方面具有很高的生物学和临床重要性，但仍缺乏足够的研究工具。这里，建立了基于偏微分方程（PDE）的数学模型，该模型模拟了细胞消融的过程。该模型表明了每个细胞如何通过吸收或分泌可扩散因子而对微环境做出贡献，并量化了可以通过扩散介导的信号解释观察到的强度的程度。该模型允许从直接物理接触和硬接线（epi）遗传差异介导的反应的综合影响中分离出肿瘤微环境中对信号梯度的表型反应。该方法应用于多通道免疫荧光原位杂交（iFISH）染色的乳腺癌组织学标本，并研究了相关性：HER2基因扩增，HER2蛋白的表达和细胞与可扩散微环境的相互作用。这种方法可以对复杂输入进行部分反卷积，从而形成肿瘤细胞表型异质性，并识别出显着影响信号分子梯度的细胞。