Regulation of Collective Metastasis by Nanolumenal Signaling

• Published in: Cell Vol. 183; no. 2; pp. 395 - 410.e19
• Main Authors: Wrenn, Emma D., Yamamoto, Ami, Moore, Breanna M., Huang, Yin, McBirney, Margaux, Thomas, Aaron J., Greenwood, Erin, Rabena, Yuri F., Rahbar, Habib, Partridge, Savannah C., Cheung, Kevin J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2020
• Subjects: Animals; basal-like 2 breast cancer; Breast Neoplasms - physiopathology; Cell Adhesion - physiology; Cell Line, Tumor; Cell Movement - physiology; collective invasion; collective metastasis; collective signaling; CTC clusters; epigen; Epigen - metabolism; Epithelial-Mesenchymal Transition - genetics; Humans; Intercellular Junctions - pathology; Mice; nanolumenal signaling; nanolumina; Neoplasm Metastasis - physiopathology; Neoplastic Cells, Circulating - pathology; Signal Transduction - physiology; Triple Negative Breast Neoplasms - pathology; triple-negative breast cancer; tumor cell clusters; basal-like 2 breast cancer; CTC clusters; triple-negative breast cancer; epigen; tumor cell clusters; collective invasion; collective signaling; nanolumina; collective metastasis; nanolumenal signaling
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.08.045

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. [Display omitted] •Breast tumor cell clusters contain nanolumina—sealed, intercellular cavities•Clusters produce the growth factor epigen and concentrate it in nanolumina•Epigen is regulated during metastasis, and its suppression reduces outgrowth•Basal-like 2 breast cancer clusters highly express epigen and form nanolumina Nanolumina encased within clusters of tumor cells harbor signaling molecules that promote metastasis.