Exploring the Role of Osteosarcoma-Derived Extracellular Vesicles in Pre-Metastatic Niche Formation and Metastasis in the 143-B Xenograft Mouse Osteosarcoma Model.

Alekhya Mazumdar,Fabian E Egli,Aleksandar Boro,Patrick K Jaeger,Jess G Snedeker,Barbara Niederöst,Ana Gvozdenovic,Joaquin Urdinez,Bruno Fuchs,Roman Muff,Matthias J E Arlt,Greta Moschini

doi:10.3390/cancers12113457

Alekhya Mazumdar, Fabian E Egli + Show 10 more

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https://doi.org/10.3390/cancers12113457

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Abstract

Simple SummaryOsteosarcoma is an aggressive bone cancer that frequently metastasizes to the lungs and is the second leading cause of cancer-associated death in children and adolescents. Therefore, deciphering the biological mechanisms that mediate osteosarcoma metastasis is urgently needed in order to develop effective treatment. The aim of our study was to shed light on the primary tumor-induced changes in the lungs prior to osteosarcoma cell arrival using a xenograft osteosarcoma mouse model. Furthermore, we investigated the functional role of osteosarcoma-derived extracellular vesicles in pre-metastatic niche formation and metastasis. We showed that the primary tumor initiates an influx of CD11b+ myeloid cells in the pre-metastatic lungs. Furthermore, we demonstrated that osteosarcoma-derived extracellular vesicles alone can recapitulate myeloid cell infiltration in the lungs of naïve mice, but are insufficient to promote osteosarcoma metastasis. Our findings provide valuable insight into the field of osteosarcoma-derived extracellular vesicles and their role in pre-metastatic niche formation in the 143-B osteosarcoma model.The pre-metastatic niche (PMN) is a tumor-driven microenvironment in distant organs that can foster and support the survival and growth of disseminated tumor cells. This facilitates the establishment of secondary lesions that eventually form overt metastasis, the main cause of cancer-related death. In recent years, tumor-derived extracellular-vesicles (EVs) have emerged as potentially key drivers of the PMN. The role of the PMN in osteosarcoma metastasis is poorly understood and the potential contribution of osteosarcoma cell-derived EVs to PMN formation has not been investigated so far. Here, we characterize pulmonary PMN development using the spontaneously metastasizing 143-B xenograft osteosarcoma mouse model. We demonstrate the accumulation of CD11b+ myeloid cells in the pre-metastatic lungs of tumor-bearing mice. We also establish that highly metastatic 143-B and poorly metastatic SAOS-2 osteosarcoma cell-derived EV education in naïve mice can recapitulate the recruitment of myeloid cells to the lungs. Surprisingly, despite EV-induced myeloid cell infiltration in the pre-metastatic lungs, 143-B and SAOS-2 EVs do not contribute towards the 143-B metastatic burden in the context of both spontaneous as well as experimental metastasis in severe-combined immunodeficient (SCID) mice. Taken together, OS-derived EVs alone may not be able to form a functional PMN, and may perhaps require a combination of tumor-secreted factors along with EVs to do so. Additionally, our study gives a valuable insight into the PMN complexity by providing the transcriptomic signature of the premetastatic lungs in an osteosarcoma xenograft model for the first time. In conclusion, identification of regulators of cellular and molecular changes in the pre-metastatic lungs might lead to the development of a combination therapies in the future that interrupt PMN formation and combat osteosarcoma metastasis.

Highlights

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents with a high propensity for pulmonary metastases [1]
In order to elucidate the effects of primary tumor cells on the lung tissue prior to metastatic cell arrival, we first set out to determine the duration of the pre-metastatic phase in our established xenograft spontaneous metastasis model of osteosarcoma
More importantly, the lungs were cleared of tumor cells 4 days after tumor cell injection (TCI) (Figure S1) indicating that the leaked cells were unable to survive in the lungs due to the absence of a metastasis-supportive environment or pre-metastatic niche (PMN), underlining the importance of the PMN formation for the subsequent development of metastases

Summary

Introduction

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents with a high propensity for pulmonary metastases [1]. Metastasis is a complex multistep process and it is becoming clear that successful metastasis is not solely dictated by the autonomous properties of tumor cells such as genetic mutations or epigenetic regulation, and by their complex interplay with host components as well as the landscape of the metastatic microenvironment [2,3,4,5]. It is well-established that primary tumors release factors that orchestrate the preparation of the local parenchyma at future metastatic sites prior to the seeding of cancer cells and thereby regulate the formation of a specialized microenvironment, designated as the pre-metastatic niche (PMN) [6]. These tumor-driven stromal alterations provide a hospitable microenvironment that supports the survival and outgrowth of disseminated tumor cells leading to metastatic colonization

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