Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA.
Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Cell. 2020 Oct 15;183(2):395-410.e19. doi: 10.1016/j.cell.2020.08.045. Epub 2020 Oct 1.
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.
集体转移被定义为多细胞肿瘤细胞簇的黏附迁移和转移。破坏各种细胞黏附基因显著降低了簇形成和定植效率，但集群传递的下游信号在很大程度上仍然未知。在这里，我们使用小鼠和人乳腺癌模型来确定支持转移定植的肿瘤细胞簇产生的集体信号。我们表明，肿瘤细胞簇产生生长因子 Epigen，并将其集中在由细胞-细胞连接密封的纳米腔-细胞间隔室中，这些连接由微绒毛样突起排列。Epigen 敲低可显著降低转移性生长，并使簇从增殖状态转变为集体迁移状态。基底样 2 型，但不是间充质样，三阴性乳腺癌细胞系的肿瘤细胞簇中 Epigen 的表达增加，纳米腔被密封，纳米腔连接中断后，生长受到抑制。我们提出，纳米腔信号可能为侵袭性转移性乳腺癌提供治疗靶点。
