During progression from carcinoma in situ to an invasive tumor, the immune system is engaged in complex sets of interactions with various tumor cells. Tumor cell plasticity also alters disease trajectories via epithelial-to-mesenchymal transition (EMT). Several of the same pathways that regulate EMT are involved in tumor-immune interactions, yet little is known about the mechanisms and consequences of crosstalk between these regulatory processes. Here we introduce a multiscale evolutionary model to describe tumor-immune-EMT interactions and their impact on epithelial cancer progression from in situ to invasive disease. Through in silico analyses of large patient cohorts, we find controllable regions that maximize invasion-free survival. We identify that delaying tumor progression depends crucially on properties of the mesenchymal tumor cell phenotype: its growth rate and its immune-evasiveness. Through analysis of EMT-inflammation-associated data from The Cancer Genome Atlas, we find that association with EMT significantly worsens invasion-free survival probabilities in support of our model, and we predict new genes influencing outcomes in bladder and uterine cancer, including FGF pathway members. These results offer novel means to delay disease progression by regulating properties of EMT through specific gene interactions, and demonstrate the importance of studying cancer-immune interactions in light of EMT.

中文翻译：

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模拟EMT免疫动力学对上皮癌进展的影响

在从原位癌发展为浸润性肿瘤的过程中，免疫系统会与各种肿瘤细胞发生复杂的相互作用。肿瘤细胞的可塑性也通过上皮-间质转化（EMT）改变疾病的轨迹。调节EMT的几种相同途径也参与了肿瘤-免疫相互作用，但对这些调节过程之间的串扰的机制和后果知之甚少。在这里，我们介绍了一种多尺度进化模型来描述肿瘤-免疫-EMT相互作用及其对上皮癌从原位转移到浸润性疾病的影响。通过对大型患者队列进行计算机分析，我们发现可控区域可最大程度地提高无侵袭生存率。我们发现，延迟肿瘤进展关键取决于间充质肿瘤细胞表型的特性：其生长速度和免疫逃避性。通过对癌症基因组图谱中与EMT炎症相关的数据的分析，我们发现与EMT的相关性显着恶化了无侵袭性生存概率，从而为我们的模型提供了支持，并且我们预测了影响膀胱癌和子宫癌预后的新基因，包括FGF途径成员。这些结果提供了通过特定基因相互作用调节EMT特性来延迟疾病进展的新颖手段，并证明了根据EMT研究癌症-免疫相互作用的重要性。我们发现与EMT的关联显着恶化了支持我们模型的无侵袭性生存概率，并且我们预测了影响FGF和FGF等膀胱癌和子宫癌预后的新基因。这些结果提供了通过特定基因相互作用调节EMT特性来延迟疾病进展的新颖手段，并证明了根据EMT研究癌症-免疫相互作用的重要性。我们发现与EMT的关联显着恶化了支持我们模型的无侵袭性生存概率，并且我们预测了影响FGF和FGF等膀胱癌和子宫癌预后的新基因。这些结果提供了通过特定基因相互作用调节EMT特性来延缓疾病进展的新颖手段，并证明了根据EMT研究癌症与免疫相互作用的重要性。