Abstract
Understanding how heterogeneous cancer cell populations migrate collectively is of paramount importance to arrest metastasis. Here, we applied 3D culture-based approaches for in vitro modeling of the collective migration of squamous carcinoma cells and examine the impact of epithelial and mesenchymal cell interactions on this type of migration. We show that both mesenchymal N-cadherin-expressing cancer cells and cancer-associated fibroblasts cooperate in collective migration of epithelial cancer cells by leading their collective migration. This was consistent with the observed distribution of E-cadherin/N-cadherin in the human carcinoma tissues of head and neck. The presence of “leader” mesenchymal cancer cells or “leader” fibroblasts was significantly associated with metastasis development, recurrent disease and low overall disease survival in head and neck squamous cell carcinomas (HNSCC). In silico analysis of independent public datasets revealed that increased N-cadherin expression in the heterogeneous cancer tissues is associated with disease progression not only in HNSCC but also in other prevalent tumors, such as colorectal, breast and lung cancer. Collectively, our data highlight the importance of mesenchymal cells in collective cell migration and disease progression, findings that may have a broad significance in cancer, especially in those in which aberrant N-cadherin expression negatively impacts disease survival.
Highlights
Tumor metastases are responsible for as much as 90% of all cancer-related deaths, yet it remains the most poorly understood feature of cancer pathogenesis
Our in vitro model system of collective cell migration cells has revealed for the first time that, when epithelial E+/CK+ and mesenchymal N+/VIM + squamous cell carcinomas (SCC) cells cohabit, N+VIM+ cells act as leaders of the collective cell migration dragging E+CK+ cells with them
We show for the first time that these results are consistent with the topographic distribution of N+ cancer cells and cancer associated fibroblasts (CAFs) observed in head and neck SCC tissues that had metastatic behavior
Summary
Tumor metastases are responsible for as much as 90% of all cancer-related deaths, yet it remains the most poorly understood feature of cancer pathogenesis. Two distinct patterns of tumor cell invasion have been described: single-cell migration, leading to dissemination of individual tumor cells, and collective migration, resulting in multi-cellular cancer cell clusters [1,2,3]. Epithelial-to-mesenchymal transition (EMT) has been proposed as the critical mechanism for the acquisition of metastatic phenotypes by epithelial cancer cells that invade as single cells [4,5,6]. EMT, epithelial cells disrupt tight cell–cell contacts and activate mesenchymal programs acquiring a fibroblast-like morphology with increased invasiveness and cell–stroma interactions, leading to the dissemination of single tumor cells. E-cadherin expression, which results in weakened cell junctions followed by cell detachment and the onset of a single-cell mode of migration. E-cadherin loss is frequently coupled with increased
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