Institut Curie, Laboratory of Genetics and Developmental Biology, PSL Research University, INSERM U934, CNRS UMR3215, Paris, France.
Sorbonne University, UPMC University of Paris VI, Paris, France.
Elife. 2022 May 11;11:e76541. doi: 10.7554/eLife.76541.
Tumours are complex ecosystems composed of different types of cells that communicate and influence each other. While the critical role of stromal cells in affecting tumour growth is well established, the impact of mutant cancer cells on healthy surrounding tissues remains poorly defined. Here, using mouse intestinal organoids, we uncover a paracrine mechanism by which intestinal cancer cells reactivate foetal and regenerative YAP-associated transcriptional programmes in neighbouring wildtype epithelial cells, rendering them adapted to thrive in the tumour context. We identify the glycoprotein thrombospondin-1 (THBS1) as the essential factor that mediates non-cell-autonomous morphological and transcriptional responses. Importantly, Thbs1 is associated with bad prognosis in several human cancers. This study reveals the THBS1-YAP axis as the mechanistic link mediating paracrine interactions between epithelial cells in intestinal tumours.
肿瘤是由不同类型的细胞组成的复杂生态系统，这些细胞相互交流并影响彼此。虽然基质细胞在影响肿瘤生长方面的关键作用已得到充分证实，但突变癌细胞对健康周围组织的影响仍未得到明确界定。在这里，我们使用小鼠肠道类器官，揭示了一种旁分泌机制，即肠道癌细胞在邻近的野生型上皮细胞中重新激活胎儿和再生的 YAP 相关转录程序，使它们适应肿瘤环境中的生长。我们确定糖蛋白血小板反应蛋白-1（THBS1）是介导非细胞自主形态和转录反应的必需因素。重要的是，Thbs1 与几种人类癌症的不良预后相关。这项研究揭示了 THBS1-YAP 轴作为介导肠道肿瘤上皮细胞旁分泌相互作用的机制联系。
