Journal Article

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

Brogi, Edi, Schachner, Melitta, Ganesh, Karuna, Boire, Adrienne, Massagué, Joan, Valiente, Manuel, Rosenblum, Marc, Giancotti, Filippo G., Er, Ekrem Emrah, Agrawal, Saloni, Griscom, Bailey, Hu, Jing, Zou, Yilong, Malladi, Srinivas

2018

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 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