Abstract
Atypical teratoid/rhabdoid tumor (ATRT) is a rare pediatric brain tumor with extremely high aggressiveness and poor prognosis. The tumor microenvironment is regulated by a complex interaction among distinct cell types, yet the crosstalk between tumor-associated mesenchymal stem cells (tMSCs) and naïve ATRT cells are unclear. In this study, we sought to identify the secretory factor(s) that is responsible for the tMSC-mediated regulation of ATRT migration. Comparing with ATRT cell alone, co-culture of tMSCs or addition of its conditioned medium (tMSC-CM) promoted the migration of ATRT, and this effect could be abrogated by exosome release inhibitor GW4869. The exosomes in tMSC-CM were detected by transmission electron microscope and flow cytometry. ATRT naïve cell-derived conditioned media (ATRT-CM) also enhanced the exosome secretion from tMSCs, indicating the interplay between ATRT cells and tMSCs. Microarray analysis revealed that, compared with that in bone marrow-derived MSCs, microRNA155 is the most upregulated microRNA in the tMSC-CM. Tracing the PK67-labeled exosomes secreted from tMSCs confirmed their incorporation into naïve ATRT cells. After entering ATRT cells, miR155 promoted ATRT cell migration by directly targeting SMARCA4. Knockdown of SMARCA4 mimicked the miR155-driven ATRT cell migration, whereas SMARCA4 overexpression or the delivery of exosomes with miR155 knockdown suppressed the migration. Furthermore, abrogation of exosome release with GW4869 reduced the tumorigenesis of the xenograft containing naïve ATRT cells and tMSCs in immunocompromised recipients. In conclusion, our data have demonstrated that tMSCs secreted miR155-enriched exosomes, and the exosome incorporation and miR155 delivery further promoted migration in ATRT cells via a SMARCA4-dependent mechanism.
Highlights
An extremely aggressive and highly malignant embryonal central nervous system tumor, atypical teratoid rhabdoid tumor (ATRT), accounts for 1%–2% of all pediatric tumors [1]
To identify which cancer-associated stromal cells involved in the regulation of malignancy of Atypical teratoid/rhabdoid tumor (ATRT), various types of stromal cells including tumor-associated mesenchymal stem cells (tMSCs), human umbilical vein endothelial cells, THP1- and U937 monocytes were co-cultured with two different ATRT cell lines (ATRT-1 and ATRT-2) [21,22,24,25] for a wound healing migration assay (Figure 1)
Cell lines and resulted in more than 80% coverage of the created wound-healing space (Figure 1A,B). These results suggested a crucial role of tMSCs in the tumor microenvironment to promote the migratory ability of ATRT cells
Summary
An extremely aggressive and highly malignant embryonal central nervous system tumor, atypical teratoid rhabdoid tumor (ATRT), accounts for 1%–2% of all pediatric tumors [1]. ATRT is a rare tumor that predominantly affects children younger than three years old, with only a few cases in adults [2,3], and usually carries extremely poor overall survival [2]. Despite the advanced cancer treatment, the standard therapy for ATRT is usually ineffective. High-dose chemotherapy may be an alternative approach to radiation therapy. This approach has a poor outcome with relatively high rates of recurrence and usually requires repeated surgery and chemotherapy. Recent studies have shown that tumor progression is the major leading cause of mortality in ATRT patients [5]
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