2021年10月12日，《细胞》杂志在线发表了加拿大多伦多大学Rama Khokha等研究人员的合作成果。该研究揭示了胰腺癌的空间局限性亚肿瘤微环境。
研究人员通过大规模整合组织学指导下的区域性多器官功能障碍，以及临床数据和患者衍生的临床前模型，来解读了人类胰腺肿瘤微环境（TME）。研究人员发现了"亚TME"，即以成纤维细胞可塑性为基础的、在组织学上可定义的组织状态，与肿瘤免疫、亚型、分化和治疗反应有区域关系。富含复杂但功能协调的成纤维细胞群的"反应型"亚TME是热免疫的，并由侵略性的肿瘤细胞表型驻扎。
富含基质的"被遗弃的"亚TME包含较少的活化成纤维细胞和肿瘤抑制特征，但具有明显的化疗保护作用，并在化疗时富集。亚TME起源于成纤维细胞的分化轨迹，在单细胞转录组学和原位都有明显的过渡性状态。亚TME的瘤内共存产生了病人特有的表型和计算上可预测的异质性，与恶性生物学紧密相连。因此，丰富的、臭名昭著的胰腺TME内异质性不是随机的，而是标志着基本的组织单位。
据悉，肿瘤内异质性是了解TME如何推动恶性肿瘤进展的一个关键前沿问题。
附：英文原文
Title: Spatially confined sub-tumor microenvironments in pancreatic cancer
Author: Barbara T. Grünwald, Antoine Devisme, Geoffroy Andrieux, Foram Vyas, Kazeera Aliar, Curtis W. McCloskey, Andrew Macklin, Gun Ho Jang, Robert Denroche, Joan Miguel Romero, Prashant Bavi, Peter Bronsert, Faiyaz Notta, Grainne O’Kane, Julie Wilson, Jennifer Knox, Laura Tamblyn, Molly Udaskin, Nikolina Radulovich, Sandra E. Fischer, Melanie Boerries, Steven Gallinger, Thomas Kislinger, Rama Khokha
Issue&Volume: 2021-10-12
Abstract: 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.
DOI: 10.1016/j.cell.2021.09.022
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01105-3