Distinct Roles of Tumor-Associated Mutations in Collective Cell Migration

Abstract

Recent evidence suggests that groups of cells are more likely to form clinically dangerous metastatic tumors, emphasizing the importance of understanding mechanisms underlying collective behavior. The emergent collective behavior of migrating cell sheets in vitro has been shown to be disrupted in tumorigenic cells but the connection between this behavior and in vivo tumorigenicity is unclear. Here we use particle image velocimetry to measure a multi-dimensional collective migration phenotype for genetically defined cell lines that range in their in vivo behavior from non-tumorigenic to aggressively metastatic. By using cells with controlled mutations, we show that PTEN deletion enhances collective migration, while Ras activation suppresses it, even when combined with PTEN deletion. These opposing effects on collective migration phenotype of two mutations that are frequently found in patient tumors could be exploited in clinical assessments of metastatic potential or in the development of novel treatments for metastatic disease.

Learning the dynamics of cell–cell interactions in confined cell migration

“…At the single-cell level, MDA-MB-231 cells are known to be more invasive than MCF10A cells ( 48 , 49 ) and express lower levels of the cell–cell adhesion protein E-cadherin ( 19 , 50 ), possibly underlying the different friction-like interactions we found for these cell lines. These two cell lines also display remarkably different collective behaviors ( 51 – 53 ): MCF10A cells in two-dimensional (2D) epithelial sheets exhibit aligned, directed motion and form compact spheroids in three-dimensional (3D) culture, with few invasive branches. In contrast, MDA-MB-231 cells in 2D epithelial sheets exhibit nonaligned, random motion and form invasive, noncontiguous clusters in 3D culture, with significant single-cell dispersion from the cluster.…”

Mutational drivers of cancer cell migration and invasion

“…102 Overexpression of KRAS G12V leads to a decrease of collective invasion of MCF10A cells. 103 Mutations in genes encoding downstream effectors of Ras GTPases also affect the ability of tumour cells to move. The BRAF V600E driver mutation occurs in almost half of all melanoma cases and enhances the kinase activity of the BRAF protein.…”

“…Interestingly, the double PTEN and KRAS mutant cells show decreased collective behaviour, suggesting that KRAS dominates the collective migration phenotype. 103 GOF mutations in PTEN are also known to modulate tumour cell movement. For example, the A126G mutant promotes the migration of PC3 prostate cancer cells in vitro.…”

Learning the dynamics of cell-cell interactions in confined cell migration

“…At the single-cell level, MDA-MB-231 cells are known to be more invasive than MCF10A cells [48,49], and express lower levels of the cell-cell adhesion protein E-cadherin [19,50], possibly underlying the different friction-like interactions we found for these cell lines. These two cell lines also display remarkably different collective behaviors [51][52][53]: MCF10A cells in 2D epithelial sheets exhibit aligned, directed motion and form compact spheroids in 3D culture, with few invasive branches. In contrast, MDA-MB-231 cells in 2D epithelial sheets exhibit non-aligned, random motion and form invasive, non-contiguous clusters in 3D culture, with significant single-cell dispersion from the cluster.…”