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Osteosarcoma cells-derived secretome induce pre-metastatic changes in the lung microenvironment that support lung metastasis formation

ABSTRACT: To investigate the molecular and cellular alterations occurring in the lung tissue during the pre-metastatic niche formation in osteosarcoma, we used two different approaches in which mice were implanted subcutaneously with the 143B OS cells for a primary tumour (PT) formation or treated with the 143B cell-derived secretome (SCR) to mimic the release of secreted factors by a locally primary tumour.

ORGANISM(S): Mus musculus

PROVIDER: GSE216744 | GEO | 2023/12/06

REPOSITORIES: GEO

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Project description:Background: Radiation therapy is the standard of care for central nervous system tumours. Despite the success of radiation therapy in reducing tumour mass, irradiation (IR)-induced vasculopathies and neuroinflammation contribute to late-delayed complications, neurodegeneration, andpremature ageing in long-term cancer survivors. Mesenchymal stromal cells (MSCs) are adult stem cells that facilitate tissue integrity, homeostasis, and repair. Here, we investigated the potential of the iPSC-derived MSC(iMSC) secretome in immunomodulation and vasculature repair in response to radiation injury utilizing human cell lines. Methods: We generated iPSC-derived iMSC lines and evaluated the potential of their conditioned media (iMSC CM) to treat IR-induced injuries in human monocytes (THP1) and brain vascular endothelial cells (hCMEC/D3). We further assessed factors in the iMSC secretome, their modulation, and the molecular pathways they elicit. Results: Increasing doses of IR disturbed endothelial tube and spheroid formation in hCMEC/D3. When IR-injured hCMEC/D3 (IR ≤ 5 Gy) were treated with iMSC CM, endothelial cell viability, adherence, spheroid compactness, and proangiogenic sprout formation were significantly ameliorated, and IR-induced ROS levels were reduced. iMSC CM augmented tube formation in cocultures of hCMEC/D3 and iMSCs. Consistently, iMSC CM facilitated angiogenesis in a zebrafish model in vivo. Furthermore, iMSC CM suppressed IR-induced NFκB activation, TNF-α release, and ROS production in THP1 cells. Additionally, iMSC CM diminished NF-kB activation in THP1 cells cocultured with irradiated hCMEC/D3, iMSCs, or HMC3 microglial lines. The cytokine array revealed that iMSC CM contains the proangiogenic and immunosuppressive factors MCP1/CCL2, IL6, IL8/CXCL8, ANG (Angiogenin), GROα/CXCL1, and RANTES/CCL5. Common promoter regulatory elements were enriched in TF-binding motifs such as androgen receptor (ANDR) and GATA2. hCMEC/D3 phosphokinome profiling revealed increased expression of pro-survival factors, the PI3K/AKT/mTOR modulator PRAS40 and β-catenin in response to CM. The transcriptome analysis revealed increased expression of GATA2 in iMSCs and the enrichment of pathways involved in RNA metabolism, translation, mitochondrial respiration, DNA damage repair, and neurodevelopment. Conclusions: The iMSC secretome is a comodulated composite of proangiogenic and immunosuppressive factors that has the potential to alleviate radiation-induced vascular endothelial cell damage and immune activation.

Project description:The immune system plays a key role in the protective response against oral cancer; however, the tumour microenvironment (TME) is able to impair this anti-cancer response by modulating T helper (Th) responses and promoting an anti-inflammatory environment. Regulatory T cells (Tregs) and Th2 effector cells (Teff) have been associated with bad prognosis in oral squamous cell carcinoma (OSCC), however, it is unknown the main immunomodulatory mechanisms associated with the enrichment of these subsets in OSCC. We characterized Th-like lineages in Tregs and Teff and evaluated the main immunomodulatory changes induced by the TME in OSCC. Our phenotypic data revealed a higher distribution of tumour-infiltrating CCR8+ and Th2-like Treg in OSCC in comparison with non-malignant samples, whereas the percentages of Th1 cells were reduced in cancer. We then analyzed the direct effect of the TME by exposing T cell subsets to cancer secretomes and we observed that the OSCC secretome induced CCR8 expression and reduced cytokine production on both subsets. Transcriptomic analysis showed that the co-culture with OSCC secretome induced several gene changes associated with the vitamin D (VitD) signaling pathway in T cells. In addition, a proteomic analysis identified the presence of several proteins associated with prostaglandin E2 (PGE2) production by rapid membrane VitD signaling and an reduce presence of the VitD binding protein. Thus, we analyzed the effect of VitD and PGE2 and we observed that VitD promote a regulatory Th2-like responses and CCR8 expression, whereas PGE2 also modulate CCR8 but inhibited cytokine production in combination with VitD. Finally, we evaluated the presence of CCR8 ligand in OSCC and we observed higher presence of chemokine CCL18, which was also able to up regulate CCR8 in activated Th cells. Overall, our data showed that the immunomodulatory changes induced by the TME regarding CCR8 expression and regulatory Th2 phenotypes are associated with PGE2 mediated VitD signaling pathway and CCL18 expression in OSCC.

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Osteosarcoma cells-derived secretome induce pre-metastatic changes in the lung microenvironment that support lung metastasis formation

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