Involvement of Actin Cytoskeletal Components in Breast Cancer Cell Fusion with Human Mesenchymal Stroma/Stem-Like Cells.

Catharina Melzer,Ralf Hass,Juliane Von Der Ohe

doi:10.3390/ijms20040876

Catharina Melzer, Ralf Hass + Show 1 more

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https://doi.org/10.3390/ijms20040876

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Abstract

Cell fusion as a rare event was observed following the co-culture of human MDA-MB-231cherry breast cancer cells or benign neoplastic MCF10Acherry breast epithelial cells together with different mesenchymal stroma/stem-like cells (MSCGFP) cultures, respectively, resulting in the generation of double-fluorescing hybrid cells. Analysis of potential molecular mechanisms for the formation of cancer hybrid cells revealed cytoskeletal components, including F-actin. Thus, a sub-lethal concentration of cytochalasin D, which blocks elongation of actin filaments, was able to significantly reduce cancer hybrid cell formation. Simultaneously, cell cycle progression of the different co-cultures remained unaffected following treatment with cytochalasin D, indicating continued proliferation. Moreover, exposure to 50 nM cytochalasin D revealed little if any effect on the expression of various integrins and cell adhesion molecules in the different co-cultures. However, LC-MS proteome analysis of the different control co-cultures compared to corresponding cytochalasin-treated co-cultures demonstrated predominant differences in the expression of actin-associated cytoskeletal proteins. In addition, the requirement of structured actin to provide an appropriate cytoskeletal network for enabling subsequent fusion processes was also substantiated by the actin filament disrupting latrunculin B, which inhibits the fusion process between the breast cancer populations and mesenchymal stroma/stem-like cells (MSC). Together, these findings suggest an important role of distinct actin structures and associated cytoskeletal components during cell fusion and the formation of breast cancer hybrid cells.

Highlights

IntroductionCancer cell fusion can generate new populations of cancer hybrid cells, either by homotypic (autofusion—the combination of cells from the same population) or heterotypic (heterofusion—the hybrid formation of different cell types) processes [1,2,3]
Cancer cell fusion can generate new populations of cancer hybrid cells, either by homotypic or heterotypic processes [1,2,3]
While heterofusion between mesenchymal stroma/stem-like cells (MSC) and neoplastic breast cells represents a rare event that occurs in 0.2% to about 1% of the co-cultured population, treatment with actin polymerization inhibitor cytochalasin D significantly reduces the rate of hybrid cell formation (Figure 1A)

Summary

Introduction

Cancer cell fusion can generate new populations of cancer hybrid cells, either by homotypic (autofusion—the combination of cells from the same population) or heterotypic (heterofusion—the hybrid formation of different cell types) processes [1,2,3]. Cancer cell fusion enables RNA and DNA transfer to non-cancer cells, such as mesenchymal stroma/stem-like cells (MSC) and vice versa, contributing to massive genomic alterations and clonal diversity [8,9,10,11,12]. This genetic change of a hybrid cell alters its fundamental biological properties and cancer cell fate. Cannibalism may represent a mechanism for hybrid cell generation whereby cancer cells can enter dormancy after cannibalizing MSC [14]

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