The regulatory effect of hyaluronan on human mesenchymal stem cells\u2019 fate modulates their interaction with cancer cells in vitro

Christian Vogeley,Sören Twarock,Özer Degistirici,Jessica Wladarz,Jens W Fischer,Roland Meisel,Katharina Gorges,Oliver Reiners,Tobias Gorges

doi:10.1038/s41598-021-00754-0

Abstract

Metastatic spread of cancer cells into a pre-metastatic niche is highly dependent on a supporting microenvironment. Human bone marrow-derived mesenchymal stem cells (bmMSCs) contribute to the tumor microenvironment and promote cancer metastasis by inducing epithelial-to-mesenchymal transition and immune evasion. The underlying mechanisms, however, are incompletely understood. The glycosaminoglycan hyaluronan (HA) is a central component of the extracellular matrix and has been shown to harbor pro-metastatic properties. In this study we investigated the highly disseminating breast cancer and glioblastoma multiforme cell lines MDA-MB-321 and U87-MG which strongly differ in their metastatic potential to evaluate the impact of HA on tumor promoting features of bmMSC and their interaction with tumor cells. We show that adipogenic differentiation of bmMSC is regulated by the HA-matrix. This study reveals that MDA-MB-231 cells inhibit this process by the induction of HA-synthesis in bmMSCs and thus preserve the pro-tumorigenic properties of bmMSC. Furthermore, we show that adhesion of MDA-MB-231 cells to bmMSC is facilitated by the tumor cell-induced HA-rich matrix and is mediated by the HA-receptor LAYN. We postulate that invasive breast cancer cells modulate the HA-matrix of bmMSC to adapt the pre-metastatic niche. Thus, the HA-matrix provides a potential novel therapeutic target to prevent cancer metastasis.

Highlights

Metastatic spread of tumor cells is a pivotal process of cancer progression and a critical prognostic factor for disease burden and patient survival
Since mesenchymal stem cells are an important factor in orchestrating the bone marrow niche and are at the same time a significant source of extracellular matrix molecules, we investigated the interplay between tumor cells of cancer entities which invariably display tumor cell dissemination but different metastatic behaviors: MDAMB-321 and U87-MG as model organisms for metastasizing breast cancer and non-metastasizing glioblastoma multiforme, respectively
Our experiments provide novel insights into tumor cell–stroma interactions that may explain the differences in metastatic potential of different tumor entities

Summary

Introduction

Metastatic spread of tumor cells is a pivotal process of cancer progression and a critical prognostic factor for disease burden and patient survival. One potential and potent way of a disseminated tumor cell (DTC) to remodel the metastatic niche would be to influence MSC plasticity. MSCs represent a particular source of ECM molecules such as hyaluronan (HA) that orchestrate regulatory tasks for maintaining the properties of the metastatic niche In previous studies, it has been shown, that MSCs surround themselves with a coat of HA bound to its receptor CD44 which has been speculated to regulate MSC plasticity. We show that metastatic breast cancer cell lines actively seek close proximity to MSCs in dependence of their HA-receptor layilin, positively modulate the MSC HA-system and prevent MSC’s lineage commitment towards adipogenic differentiation. As immunosuppressive properties of MSCs get substantially impaired after adipogenic differentiation, this might provide first hints towards the importance of the hyaluronan MSC matrix in modulating the metastatic niche of different cancer entities

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