It is estimated that only 0.02% of disseminated tumour cells are able to seed overt metastases¹. While this suggests the presence of environmental constraints to metastatic seeding, the landscape of host factors controlling this process remains largely unclear. Here, combining transposon technology² and fluorescence niche labelling³, we developed an in vivo CRISPR activation screen to systematically investigate the interactions between hepatocytes and metastatic cells. We identify plexin B2 as a critical host-derived regulator of liver colonization in colorectal and pancreatic cancer and melanoma syngeneic mouse models. We dissect a mechanism through which plexin B2 interacts with class IV semaphorins on tumour cells, leading to KLF4 upregulation and thereby promoting the acquisition of epithelial traits. Our results highlight the essential role of signals from the liver parenchyma for the seeding of disseminated tumour cells before the establishment of a growth-promoting niche. Our findings further suggest that epithelialization is required for the adaptation of CRC metastases to their new tissue environment. Blocking the plexin-B2–semaphorin axis abolishes metastatic colonization of the liver and therefore represents a therapeutic strategy for the prevention of hepatic metastases. Finally, our screening approach, which evaluates host-derived extrinsic signals rather than tumour-intrinsic factors for their ability to promote metastatic seeding, is broadly applicable and lays a framework for the screening of environmental constraints to metastasis in other organs and cancer types.

据估计，只有 0.02% 的播散性肿瘤细胞能够产生明显的转移 ¹ 。虽然这表明转移播种存在环境限制，但控制这一过程的宿主因素的情况在很大程度上仍不清楚。在此，我们结合转座子技术 ² 和荧光生态位标记 ³ ，开发了一种体内CRISPR激活屏幕，以系统地研究肝细胞与转移细胞之间的相互作用。我们确定 plexin B2 是结直肠癌、胰腺癌和黑色素瘤同基因小鼠模型中肝脏定植的关键宿主衍生调节因子。我们剖析了丛蛋白 B2 与肿瘤细胞上的 IV 类信号蛋白相互作用的机制，导致 KLF4 上调，从而促进上皮性状的获得。我们的结果强调了来自肝实质的信号对于在建立促进生长的生态位之前播散播散性肿瘤细胞的重要作用。我们的研究结果进一步表明，上皮化是结直肠癌转移适应新组织环境所必需的。阻断丛蛋白-B2-信号蛋白轴可消除肝脏的转移定植，因此代表了预防肝转移的治疗策略。最后，我们的筛选方法评估了宿主衍生的外在信号而不是肿瘤内在因素促进转移播种的能力，该方法具有广泛的适用性，并为筛选其他器官和癌症类型转移的环境限制奠定了框架。