Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications
Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications
复制标题
DOI：
10.1038/s41467-019-09307-6
复制
发表时间：
2019-03-22
影响因子：
16.6
通讯作者：
Jean, Didier
中科院分区：
文献类型：
--
作者：
Blum, Yuna;Meiller, Clement;Jean, Didier
恶性胸膜间皮瘤（MPM）被认为是异质性的基础上组织学和分子谱。组织学研究了MPM的肿瘤间和肿瘤内异质性，并描述了三种主要类型：上皮样、肉瘤样和双相，前两种类型的组合。迄今为止，分子谱研究尚未解决MPM的肿瘤内异质性。在这里，我们使用反卷积的方法，并表明分子梯度揭示了新的MPM肿瘤内的异质性，导致重新考虑MPM分子分类。我们发现，每个肿瘤可以分解为上皮样和肉瘤样成分的组合，其比例与预后高度相关。此外，我们表明，这种更微妙的方式来表征MPM异质性提供了一个更好的了解潜在的致癌途径和相关的表观遗传调控和免疫和基质的情况。我们讨论了这些发现对指导治疗策略的影响，特别是免疫治疗和靶向治疗。
Malignant pleural mesothelioma (MPM) is recognized as heterogeneous based both on histology and molecular profiling. Histology addresses inter-tumor and intra-tumor heterogeneity in MPM and describes three major types: epithelioid, sarcomatoid and biphasic, a combination of the former two types. Molecular profiling studies have not addressed intra-tumor heterogeneity in MPM to date. Here, we use a deconvolution approach and show that molecular gradients shed new light on the intra-tumor heterogeneity of MPM, leading to a reconsideration of MPM molecular classifications. We show that each tumor can be decomposed as a combination of epithelioid-like and sarcomatoid-like components whose proportions are highly associated with the prognosis. Moreover, we show that this more subtle way of characterizing MPM heterogeneity provides a better understanding of the underlying oncogenic pathways and the related epigenetic regulation and immune and stromal contexts. We discuss the implications of these findings for guiding therapeutic strategies, particularly immunotherapies and targeted therapies.