INTRODUCTION: Atypical teratoid/rhabdoid tumor (AT/RT) is a primary pediatric tumor entity of the central nervous system showing intra- and intertumoral heterogeneity concerning the molecular landscape and cellular composition. Myeloid cells are considered key orchestrators of the immunological tumor microenvironment (TME) of AT/RT. Tumor-infiltrating CD68+ macrophages favor chemotherapy resistance and recurrence, and are consequently related to a poor patient outcome. METHODS: Using single-cell RNA sequencing (scRNA-seq) of human and murine AT/RT samples, multiplex immunohistochemistry, depletion of myeloid cells in mouse models and advanced cell culture models for myeloid tumor cell communication, we obtained deeper mechanistic insight into these cell-cell interactions. RESULTS: Infiltrating CD68+ macrophages interact with AT/RT tumor cells generating intermediary hybrid-like cells with autonomous communication properties, increasing the cell heterogeneity of AT/RT. By depletion of myeloid cells in AT/RT mouse models followed by scRNA-seq of tumor and non-tumor samples, we demonstrated that tumor formation is hindered. Furthermore, we give mechanistic insights into how myeloid cells contribute to tumorigenesis. IN CONCLUSION: the dynamic and extensive interactions between tumor cells and myeloid cells do not only potentiate cellular heterogeneity but might also induce cellular plasticity associated with the acquisition of resistance to chemotherapy and seem to be essential for AT/RT development.
BACKGROUND: Treatment-related long-term sequelae and chemotherapy resistance diminish the success of retinoblastoma (RB) treatment. To unravel the mechanisms leading to tumor progression and resistance we examined the intratumoral cellular heterogeneity of RB and its interactions with cells of the tumor microenvironment (TME). METHODS: We used single-cell RNA (scRNA-seq) and ATAC sequencing (scATAC-seq) as well as spatial transcriptomics to analyze and compare RB samples from patients with or without previous chemotherapy (chemo-treated vs. naïve). In addition, we developed a 3D model by injection of RB and TME cells into retinal organoids, which mimics the heterogeneous surrounding of the tumor in a spatially and functionally organized manner. RESULTS: ScRNA-seq revealed a high intratumoral heterogeneity of tumor cells representing distinct developmental stages from progenitors to more differentiated photoreceptor cells. The predominant cell type in the TME was M2-activated microglia (MG). M2-MG exerted multiple receptor-ligand interactions with RB tumor cells which were not found in non-diseased retinas. These tumor-specific cellular interactions regulate multiple signaling pathways (e. g. VEGF-, WNT-, BMP-, PGF- signaling) known to be involved in RB progression. By comparing chemo-treated and chemo-naïve RB samples we were able to identify treatment-resistant and -sensitive subpopulations of tumor cells. Finally, data from our RB-retina in vitro model highlighted the impact of RB cells on gene expression programs of normal retinal cells. CONCLUSION: In summary, we deciphered the intratumoral heterogeneity of RB, uncovered an intricate network of microglia-tumor cell interactions that connects numerous important signaling pathways, and further identified chemotherapy-resistant/sensitive tumor cell populations. The latter observation could prove to be very helpful in the development of novel therapeutic approaches in the treatment of RB.
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