Cell shape, and not 2D migration, predicts extracellular matrix-driven 3D cell invasion in breast cancer

Abstract

Metastasis, the leading cause of death in cancer patients, requires the invasion of tumor cells through the stroma in response to migratory cues, in part provided by the extracellular matrix (ECM). Recent advances in proteomics have led to the identification of hundreds of ECM proteins, which are more abundant in tumors relative to healthy tissue. Our goal was to develop a pipeline to easily predict which ECM proteins are more likely to have an effect on cancer invasion and metastasis. We evaluated the effect of four ECM proteins upregulated in breast tumor tissue in multiple human breast cancer cell lines in three assays. There was no linear relationship between cell adhesion to ECM proteins and ECM-driven 2D cell migration speed, persistence, or 3D invasion. We then used classifiers and partial-least squares regression analysis to identify which metrics best predicted ECM-driven 2D migration and 3D invasion responses. We find that ECM-driven 2D cell migration speed or persistence did not predict 3D invasion in response to the same cue. However, cell adhesion, and in particular cell elongation and shape irregularity, accurately predicted the magnitude of ECM-driven 2D migration and 3D invasion. Our models successfully predicted the effect of novel ECM proteins in a cell-line specific manner. Overall, our studies identify the cell morphological features that determine 3D invasion responses to individual ECM proteins. This platform will help provide insight into the functional role of ECM proteins abundant in tumor tissue and help prioritize strategies for targeting tumor-ECM interactions to treat metastasis.

Inhomogeneities in 3D Collagen Matrices Impact Matrix Mechanics and Cancer Cell Migration

“…The invasion of cancer cells is a complex process. The change of the cell shape (Lyons et al, 2016;Baskaran et al, 2020), the softening the cell body and/or the nucleus (Fischer et al, 2020), the enzymatic-degradation of the matrix (Gialeli et al, 2011;Wolf and Friedl, 2011), the switch between migration modes (Friedl and Wolf, 2010) are some of well-founded methods that cancer cells use to overcome steric barriers and thus efficiently invade confined networks.…”

Decellularized extracellular matrix scaffolds identify full-length collagen VI as a driver of breast cancer cell invasion in obesity and metastasis

“…Cell-ECM responses are studied in vitro using recombinant proteins, evaluating cell adhesion to, migration on, and invasion in individual ECM proteins. We have recently shown that cell shape when a cell is adhering to ECM protein is more predictive of three-dimensional (3D) invasion in response to that same protein than migration on the same 2D substrate ( 19 ). While these assays are informative and can be used to dissect the signaling pathways involved in ECM-driven responses, they also only evaluate response to a single cue.…”

Potassium channel-driven bioelectric signaling regulates metastasis in triple-negative breast cancer

“…Together, these results demonstrate that K + channel-driven RMP hyperpolarization drives significant changes in gene expression, upregulation of pathways involved in cell adhesion. The observed upregulation of genes involved in cell adhesion suggests that overexpression of K + channels may alter the adhesion and morphology of TNBC cells, which our lab and others have demonstrated is highly predictive of 3D invasive behavior driving metastasis 34,35 . We characterized cell area and morphology of MDA-MB-231 K + overexpressing lines cultured on collagen I-coated glass plates.…”