Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79110 Freiburg, Germany.
Cell. 2021 Oct 28;184(22):5577-5592.e18. doi: 10.1016/j.cell.2021.09.022. Epub 2021 Oct 12.
Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. Here, we deconvolute the human pancreatic TME through large-scale integration of histology-guided regional multiOMICs with clinical data and patient-derived preclinical models. We discover "subTMEs," histologically definable tissue states anchored in fibroblast plasticity, with regional relationships to tumor immunity, subtypes, differentiation, and treatment response. "Reactive" subTMEs rich in complex but functionally coordinated fibroblast communities were immune hot and inhabited by aggressive tumor cell phenotypes. The matrix-rich "deserted" subTMEs harbored fewer activated fibroblasts and tumor-suppressive features yet were markedly chemoprotective and enriched upon chemotherapy. SubTMEs originated in fibroblast differentiation trajectories, and transitory states were notable both in single-cell transcriptomics and in situ. The intratumoral co-occurrence of subTMEs produced patient-specific phenotypic and computationally predictable heterogeneity tightly linked to malignant biology. Therefore, heterogeneity within the plentiful, notorious pancreatic TME is not random but marks fundamental tissue organizational units.
肿瘤内异质性是理解肿瘤微环境（TME）如何推动恶性进展的一个关键前沿领域。在这里，我们通过大规模整合组织学指导的区域性多组学与临床数据和患者衍生的临床前模型，对人类胰腺 TME 进行解卷积。我们发现了“亚 TME”，这是一种在成纤维细胞可塑性基础上定义的组织状态，与肿瘤免疫、亚型、分化和治疗反应具有区域性关系。富含复杂但功能协调的成纤维细胞群落的“反应性”亚 TME 是免疫热点，并且存在侵袭性肿瘤细胞表型。富含基质的“荒芜”亚 TME 含有较少的激活成纤维细胞和肿瘤抑制特征，但具有明显的化疗保护作用，并在化疗后富集。亚 TME 起源于成纤维细胞分化轨迹，在单细胞转录组学和原位中都可以观察到短暂状态。亚 TME 在肿瘤内的共存产生了与恶性生物学紧密相关的患者特异性表型和可计算的异质性。因此，丰富而臭名昭著的胰腺 TME 内的异质性并非随机，而是标志着基本的组织组织单位。
