Collective Polarization of Cancer Cells at the Monolayer Boundary.

Bo Li,Liu-Yuan Guan,Jian-Qing Lv,De-Qing Zhang

doi:10.3390/mi12020112

Abstract

Cell polarization, a process depending on both intracellular and intercellular interactions, is crucial for collective cell migration that commonly emerges in embryonic development, tissue morphogenesis, wound healing and cancer metastasis. Although invasive cancer cells display weak cell–cell interactions, they can invade host tissues through a collective mode. Yet, how cancer cells without stable cell–cell junctions polarize collectively to migrate and invade is not fully understood. Here, using a wound-healing assay, we elucidate the polarization of carcinoma cells at the population level. We show that with loose intercellular connections, the highly polarized leader cells can induce the polarization of following cancer cells and subsequent transmission of polarity information by membrane protrusions, leading to gradient polarization at the monolayer boundary. Unlike the polarization of epithelial monolayer where Rac1/Cdc42 pathway functions primarily, our data show that collective polarization of carcinoma cells is predominantly controlled by Golgi apparatus, a disruption of which results in the destruction of collective polarization over a large scale. We reveal that the Golgi apparatus can sustain membrane protrusion formation, polarized secretion, intracellular trafficking, and F-actin polarization, which contribute to collective cancer cell polarization and its transmission between cells. These findings could advance our understanding of collective cancer invasion in tumors.

Highlights

Collective cell migration occurs in various fundamental biological processes, including embryonic development, tissue renewal, angiogenesis, and tumor spreading [1,2,3,4,5,6,7,8,9]
By combining wound healing assay, Golgi apparatus staining, and F-actin filaments polarization analysis, we identify the mechanism underpinning the collective polarization of cancer cells with low cell–cell junctions
We find that the Golgi apparatus pathways predominate over the Rac1/Cdc42 signaling pathways in controlling the cancer cell polarization, in contrast to the polarization of healthy tissues and cells that are primarily controlled by the Rac1/Cdc42 signaling pathways

Summary

Introduction

Collective cell migration occurs in various fundamental biological processes, including embryonic development, tissue renewal, angiogenesis, and tumor spreading [1,2,3,4,5,6,7,8,9]. Cell–cell connections are mediated by intercellular junction proteins [15], which either directly or indirectly link to the cytoskeleton, providing mechanically robust and dynamic coupling between cells during their movement [16]. Stable intercellular junctions contribute to maintaining the polarity and integrity of healthy tissues. These cell–cell junctions form compact connections between neighboring cells, and those connections, together with different components of the cytoskeleton system, generate an integrated continuum across the tissue. With the help of actin-binding protein afadin (AF-6), cell junction molecules could form direct links to the cytoskeleton to regulate cell polarization in early embryonic development [21,22]. Polarized cytoskeleton and activated Cdc are essential for the polarity signal transduction

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Results

Conclusion