Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization

Metastatic 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 c...

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Veröffentlicht in:	Nature cell biology Jg. 20; H. 8; S. 966 - 978
Hauptverfasser:	Er, Ekrem Emrah, Valiente, Manuel, Ganesh, Karuna, Zou, Yilong, Agrawal, Saloni, Hu, Jing, Griscom, Bailey, Rosenblum, Marc, Boire, Adrienne, Brogi, Edi, Giancotti, Filippo G., Schachner, Melitta, Malladi, Srinivas, Massagué, Joan
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 01.08.2018 Nature Publishing Group
Schlagworte:	13/1 13/105 13/106 13/109 13/31 13/89 13/95 14/1 14/19 14/35 59 59/5 631/67 631/67/322 631/80/79/2066 631/80/86 82 Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Animals Biomedical and Life Sciences Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - secondary Cancer Cancer Research Capillaries Capillaries - metabolism Capillaries - pathology Cell Adhesion Cell adhesion & migration Cell adhesion molecules Cell Biology Cell Communication Cell Movement Cell Proliferation Cell Shape Colonization Developmental Biology Female HCT116 Cells HEK293 Cells Humans ILK protein Infiltration Integrin beta1 - genetics Integrin beta1 - metabolism Invasiveness Kinases Latency Life Sciences Male Mechanotransduction Mechanotransduction, Cellular Metastases Metastasis Mice, Inbred C57BL Mice, Inbred NOD Molecular chains Neural cell adhesion molecule Neural Cell Adhesion Molecule L1 - genetics Neural Cell Adhesion Molecule L1 - metabolism Organs Pericytes Pericytes - metabolism Pericytes - pathology Phosphoproteins - genetics Phosphoproteins - metabolism Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Proteins Signaling Spreading Stem Cells Time Factors Tissue Culture Techniques Trans-Activators - genetics Trans-Activators - metabolism Transcription Factors Tumor Microenvironment Yes-associated protein
ISSN:	1465-7392, 1476-4679, 1476-4679
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Zusammenfassung:	Metastatic 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 1 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. Massagué and colleagues show that disseminated cancer cells use L1CAM to spread on capillaries and to achieve their outgrowth through activating YAP signalling.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Undefined-3 AUTHOR CONTRIBUTIONS Current address: Brain Metastasis Group, Spanish National Cancer Research Center (CNIO), Madrid E28029, Spain (M.V); Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (F.G); Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA (S.M.) E.E.E., M.V. and J.M. conceptualized the project. E.E.E., M.V., K.G. and S.M. designed and performed the experiments. Y.Z. performed bioinformatics analyses. S.A. and B.G. assisted with the experiments. F.G. contributed to experimental design. M.S. provided the L1cam flox mice. E.B., A.B. and M.R. provided clinical samples and interpretation. E.E.E., K.G., M.V.C and J.M. wrote the manuscript.
ISSN:	1465-7392 1476-4679 1476-4679
DOI:	10.1038/s41556-018-0138-8