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Cell ; 183(2): 395-410.e19, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-33007268

RESUMEN

Collective metastasis is defined as the cohesive migration and metastasis of multicellular tumor cell clusters. Disrupting various cell adhesion genes markedly reduces cluster formation and colonization efficiency, yet the downstream signals transmitted by clustering remain largely unknown. Here, we use mouse and human breast cancer models to identify a collective signal generated by tumor cell clusters supporting metastatic colonization. We show that tumor cell clusters produce the growth factor epigen and concentrate it within nanolumina-intercellular compartments sealed by cell-cell junctions and lined with microvilli-like protrusions. Epigen knockdown profoundly reduces metastatic outgrowth and switches clusters from a proliferative to a collective migratory state. Tumor cell clusters from basal-like 2, but not mesenchymal-like, triple-negative breast cancer cell lines have increased epigen expression, sealed nanolumina, and impaired outgrowth upon nanolumenal junction disruption. We propose that nanolumenal signaling could offer a therapeutic target for aggressive metastatic breast cancers.


Asunto(s)
Neoplasias de la Mama/fisiopatología , Uniones Intercelulares/patología , Metástasis de la Neoplasia/fisiopatología , Animales , Adhesión Celular/fisiología , Línea Celular Tumoral , Movimiento Celular/fisiología , Epigen/metabolismo , Transición Epitelial-Mesenquimal/genética , Humanos , Ratones , Células Neoplásicas Circulantes/patología , Transducción de Señal/fisiología , Neoplasias de la Mama Triple Negativas/patología
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