Er, Ekrem EmrahValiente, ManuelGanesh, KarunaZou, YilongAgrawal, SaloniHu, JingGriscom, BaileyRosenblum, MarcBoire, AdrienneBrogi, EdiGiancotti, Filippo GSchachner, MelittaMalladi, SrinivasMassagué, Joan2024-12-102024-12-102018-08Nat Cell Biol . 2018 Aug;20(8):966-978.https://hdl.handle.net/20.500.12105/25872Metastatic seeding by disseminated cancer cells principally occurs in perivascular niches. Here, we show that mechanotransduction signalling triggered by the pericyte-like spreading of disseminated cancer cells on host tissue capillaries is critical for metastatic colonization. Disseminated cancer cells employ L1CAM (cell adhesion molecule L1) to spread on capillaries and activate the mechanotransduction effectors YAP (Yes-associated protein) and MRTF (myocardin-related transcription factor). This spreading is robust enough to displace resident pericytes, which also use L1CAM for perivascular spreading. L1CAM activates YAP by engaging β integrin and ILK (integrin-linked kinase). L1CAM and YAP signalling enables the outgrowth of metastasis-initiating cells both immediately following their infiltration of target organs and after they exit from a period of latency. Our results identify an important step in the initiation of metastatic colonization, define its molecular constituents and provide an explanation for the widespread association of L1CAM with metastatic relapse in the clinic.We acknowledge members of the MSKCC Molecular Cytology Core and Pathology Core Facilities for their assistance with staining, tissue processing, image acquisition and analysis and Young-Mi Kim for help with YAP activity assays. This work was supported by NIH grants P01-CA094060, P01-CA129243 (J.M.) and P30-CA008748 (Memorial Sloan Ketterin Cancer Center), T32-CA009207 (K.G.), DOD Innovator award W81XWH-12-0074 (J.M.), and the Alan and Sandra Gerry Metastasis Research Initiative (J.M.), Shulamit Katzman Endowed Postdoctoral Research Fellowships (E.E.E. and K.G.), an AACR Basic Cancer Research Fellowship and Conquer Cancer Foundation of ASCO Young Investigator Award (K.G.).engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/TRANSLATIONAL PROFILING APPROACHADHESION MOLECULECO-OPTIONGROWTHPATHWAYL1CAMTRANSCRIPTIONEXPRESSIONINDUCTIONDYNAMICSAttribution-NonCommercial-NoDerivatives 4.0 International30038252208966-978Nature Cell Biologyhttps://pmc.ncbi.nlm.nih.gov/articles/PMC6467203/pdf/nihms-1012288.pdfopen access