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.

• MeSH
• CRISPR-Cas systémy * genetika   MeSH
• fluorescence MeSH
• hepatocyty * metabolismus   cytologie   patologie   MeSH
• játra * cytologie   metabolismus   patologie   MeSH
• kolorektální nádory patologie   metabolismus   MeSH
• Krüppel-like faktor 4 metabolismus   MeSH
• lidé MeSH
• melanom metabolismus   patologie   MeSH
• metastázy nádorů * farmakoterapie   patologie   prevence a kontrola   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory jater * farmakoterapie   metabolismus   patologie   prevence a kontrola   sekundární   MeSH
• nádory slinivky břišní metabolismus   patologie   MeSH
• proteiny nervové tkáně * antagonisté a inhibitory   metabolismus   MeSH
• semaforiny antagonisté a inhibitory   metabolismus   MeSH
• transpozibilní elementy DNA MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• KLF4 protein, human MeSH Prohlížeč
• Klf4 protein, mouse MeSH Prohlížeč
• Krüppel-like faktor 4 MeSH
• PLXNB2 protein, human MeSH Prohlížeč
• Plxnb2 protein, mouse MeSH Prohlížeč
• proteiny nervové tkáně * MeSH
• semaforiny MeSH
• transpozibilní elementy DNA MeSH