Phenotypic Heterogeneity and Plasticity of Cancer Cell Migration in a Pancreatic Tumor Three-Dimensional Culture Model

Seul-Ki Kim,Seok Chung,Jong Kook Park,Hyo-Jeong Kuh,Hyunho Kim,So Dam Jang

doi:10.3390/cancers12051305

Seul-Ki Kim, Seok Chung + Show 4 more

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https://doi.org/10.3390/cancers12051305

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Abstract

Invasive cancer cell migration is a key feature of metastatic human pancreatic ductal adenocarcinoma (PDAC), yet the underlying mechanisms remain poorly understood. Here, we investigated modes of cancer cell invasion using two pancreatic cancer cell lines with differential epithelial–mesenchymal status, PANC-1 and BxPC-3, under 3D culture conditions. Multicellular tumor spheroids (TSs) were grown in a collagen matrix co-cultured with pancreatic stellate cells (PSCs) using microchannel chips. PANC-1 cells showed individual migration from TSs via invadopodium formation. BxPC-3 cells showed plasticity between collective and individual migration in either mesenchymal mode, with filopodium-like protrusions, or blebby amoeboid mode. These two cell lines showed significantly different patterns of extracellular matrix (ECM) remodeling, with MMP-dependent degradation in a limited area of ECM around invadopodia for PANC-1 cells, or MMP-independent extensive deformation of ECM for BxPC-3 cells. Cancer cell migration out of the collagen channel significantly increased by PSCs and directional cancer cell migration was mediated by fibronectin deposited by PSCs. Our results highlight the phenotypic heterogeneity and plasticity of PDAC cell migration and ECM remodeling under 3D culture conditions. This 3D co-culture model of pancreatic cancer cells and PSCs offers a useful tool for studying cancer cell migration and ECM remodeling to identify and develop potential molecular targets and anti-cancer agents against human PDAC.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all human cancers, with a 5 year survival rate of less than 6% [1]
Using our previously developed microchannel system recapitulating the in vivo tumor microenvironment [22,23], we aimed to investigate the modes of cancer cell invasion and extracellular matrix (ECM) remodeling using multicellular tumor spheroids (TSs) of two PDAC cell lines, representing a mesenchymal and epithelial cell type, cultured with pancreatic stellate cells (PSCs) in a 3D ECM environment
Under PSC co-culture, the number of spheroids increased while the spheroid diameter decreased and the number of single scattered cells significantly increased in both PANC-1 and BxPC-3 cells

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all human cancers, with a 5 year survival rate of less than 6% [1]. Matrix metalloproteinases (MMPs) are well-known factors involved in priming of the extracellular matrix (ECM) via pericellular proteolysis, which allows the cells to realign matrix fibers to pave a pathway to migration [9]. This reciprocal interaction between migrating cells and the surrounding ECM has emerged as an important mechanism for controlling the migration mode and ECM remodeling, which determines the invasion potential and progression to metastasis [10].

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