The Leader Position of Mesenchymal Cells Expressing N-Cadherin in the Collective Migration of Epithelial Cancer

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.

Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2

“…As recently reported [ 26 ], SCC38 and SCC42B cells assembled as multicellular spheroids in collagen matrix migrate as a collective unit following an outwards and downwards direction as observed upon three-dimensional reconstructions of Z-stacked images taken after 24 h of culture ( Figure 1 A).…”

“…The effect of FAK on collective cell invasion was not a cell-line-specific function. In addition to SCC42B cells, we also analyzed SCC38 cells which have greater invasive activity than SCC42B [ 26 ] and express higher levels of FAK and pFAK protein ( Figure S2 ). FRNK-induced inhibition of FAK activity in SCC38 cells (FR-SCC38) ( Figure S2 ) also impaired collective invasion (37-fold decrease in mean SCSA, p < 0.0001, Figure 1 F) compared with control cells (C-SCC38).…”

“…Indeed, clustered cohort-like cancer cell dissemination appears to be highly efficient in embolizing lymphatic and blood vessels, which are accepted as a major prognostic factor for cancer [ 25 ]. We have recently set up an in vitro system for the analysis of the collective cell migration of SCC cells in 3D systems [ 26 ]. Using that methodology, we showed 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.…”

“…However, the crosstalk of FAK and MMP-2 on the collective migration of SCC cells still remains to be well-defined. To address these issues, we used the in vitro system for the analysis of the collective cell migration in 3D systems [ 26 ] and found that in vitro collective SCC cell migration depends on the balance between FAK and MMP-2. The absence of functional FAK blocked cancer cell migration but this constrain could be released by SCC cells expressing high levels of MMP-2 or by cancer-associated fibroblasts, both of them acting as leader cells that push the immobile collective unit towards the ECM.…”

From Bench to Bedside in Tongue Muscle Cancer Invasion and Back again: Gross Anatomy, Microanatomy, Surgical Treatments and Basic Research

“…Additionally, Gopal et al identified oncofetal fibronectin (FN) as a major and obligate component of the matrix assembled by stromal fibroblasts from head and neck squamous cell carcinomas (HNSCC) [44]. Moreover, Saénz-de-Santa-María et al showed that 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 [45]. On the other hand, whether cancer cells in lymph nodes can seed distant metastases has been a subject of considerable debate.…”