INSERM U-1279, Gustave Roussy, Villejuif F-94805, France.
Institut Curie, PSL Research University, CNRS UMR 144, F-75005 Paris, France.
J Cell Sci. 2022 Jul 15;135(14). doi: 10.1242/jcs.259256. Epub 2022 Jul 25.
The metastatic progression of cancer remains a major issue in patient treatment. However, the molecular and cellular mechanisms underlying this process remain unclear. Here, we use primary explants and organoids from patients harboring mucinous colorectal carcinoma (MUC CRC), a poor-prognosis histological form of digestive cancer, to study the architecture, invasive behavior and chemoresistance of tumor cell intermediates. We report that these tumors maintain a robust apico-basolateral polarity as they spread in the peritumoral stroma or organotypic collagen-I gels. We identified two distinct topologies - MUC CRCs either display a conventional 'apical-in' polarity or, more frequently, harbor an inverted 'apical-out' topology. Transcriptomic analyses combined with interference experiments on organoids showed that TGFβ and focal adhesion signaling pathways are the main drivers of polarity orientation. Finally, we show that the apical-out topology is associated with increased resistance to chemotherapeutic treatments in organoids and decreased patient survival in the clinic. Thus, studies on patient-derived organoids have the potential to bridge histological, cellular and molecular analyses to decrypt onco-morphogenic programs and stratify cancer patients. This article has an associated First Person interview with the first author of the paper.
癌症的转移进展仍然是患者治疗中的一个主要问题。然而，这一过程背后的分子和细胞机制仍不清楚。在这里，我们使用来自患有粘液性结直肠癌 (MUC CRC) 的患者的原代外植体和类器官来研究肿瘤细胞中间产物的结构、侵袭行为和化学抗性。我们报告说，这些肿瘤在肿瘤周围基质或器官型胶原 I 凝胶中扩散时，保持着强大的顶底极性。我们确定了两种不同的拓扑结构——MUC CRC 要么显示传统的“顶向进”极性，要么更频繁地具有倒置的“顶向外”拓扑。转录组分析结合对类器官的干扰实验表明，TGFβ 和黏着斑信号通路是极性定向的主要驱动因素。最后，我们表明，顶向外拓扑与类器官中对化疗治疗的抵抗力增加以及临床中患者生存时间缩短有关。因此，基于患者来源的类器官的研究有可能将组织学、细胞和分子分析联系起来，以解密致癌形态发生程序并对癌症患者进行分层。本文附有对该论文第一作者的第一人称采访。
