Myogenic IGFBP5 levels in rhabdomyosarcoma are nourished by mesenchymal stromal cells and regulate growth arrest and apoptosis
Abstract Background Mesenchymal stromal cells belong to a diverse collection of cells in different states that are poorly characterized in soft-tissue sarcomas. In this study, we explored tumor growth-regulatory signaling between differentially educated non-malignant mesenchymal stromal cells and ma...
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BMC
2025-04-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02171-6 |
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| author | Yue Zhang Karim Katkhada Liu Zhen Meng Binbin Zhao Shanlin Tong Wiem Chaabane Aditi Kallai Nicholas P. Tobin Arne Östman Alessandro Mega Monika Ehnman |
| author_facet | Yue Zhang Karim Katkhada Liu Zhen Meng Binbin Zhao Shanlin Tong Wiem Chaabane Aditi Kallai Nicholas P. Tobin Arne Östman Alessandro Mega Monika Ehnman |
| author_sort | Yue Zhang |
| collection | DOAJ |
| description | Abstract Background Mesenchymal stromal cells belong to a diverse collection of cells in different states that are poorly characterized in soft-tissue sarcomas. In this study, we explored tumor growth-regulatory signaling between differentially educated non-malignant mesenchymal stromal cells and malignant cells in pediatric rhabdomyosarcoma (RMS). Methods Xenograft experiments demonstrated that non-malignant stromal cells influence tumor behavior. Gene expression analysis identified deregulated genes, which were further studied using cell culture assays and patient data. Clinicopathological correlations were made in a discovery cohort (N = 147) and a validation cohort (N = 101). Results The results revealed transiently suppressive paracrine effects of orthotopic stromal cells derived from skeletal muscle. These effects were lost when the stromal cells were exposed to RMS cells, either short-term in vitro, or long-term in hindlimb muscle in vivo. High resolution microarray-based Clariom D gene expression analysis identified insulin-like growth factor binding protein 5 (IGFBP5) as the top upregulated gene in RMS cells exposed to naïve stromal cells, and effects on growth arrest, caspase 3/7 activation, and myogenic cell identity were demonstrated in functional assays. Furthermore, IGFBP5 associated with the caspase 3 substrate growth arrest specific protein 2 (GAS2), lower disease stage and favorable survival in patient cohorts. Conclusions This study uses functional modeling and omics approaches to identify IGFBP5 as a candidate mediator of anti-tumor growth mechanisms originating from tumor-neighboring mesenchymal stromal cells. Tumors of mesenchymal origin, such as RMS, are known for their heterogeneity, and this could potentially pose a limitation to the study. However, a clinical relevance is emphasized by consistent findings across patient cohorts. These insights pave the way for novel therapeutic strategies modulating activities of stromal cell subsets at primary and metastatic sites in RMS. Graphical Abstract |
| format | Article |
| id | doaj-art-2c8db3f6ed0644eebf1e4f00bcfa5f0d |
| institution | DOAJ |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-2c8db3f6ed0644eebf1e4f00bcfa5f0d2025-08-20T03:18:41ZengBMCCell Communication and Signaling1478-811X2025-04-0123111810.1186/s12964-025-02171-6Myogenic IGFBP5 levels in rhabdomyosarcoma are nourished by mesenchymal stromal cells and regulate growth arrest and apoptosisYue Zhang0Karim Katkhada1Liu Zhen Meng2Binbin Zhao3Shanlin Tong4Wiem Chaabane5Aditi Kallai6Nicholas P. Tobin7Arne Östman8Alessandro Mega9Monika Ehnman10Department of Oncology-Pathology, Karolinska InstitutetDepartment of Oncology-Pathology, Karolinska InstitutetDepartment of Oncology-Pathology, Karolinska InstitutetDepartment of Oncology-Pathology, Karolinska InstitutetDepartment of Oncology-Pathology, Karolinska InstitutetDepartment of Oncology-Pathology, Karolinska InstitutetDepartment of Oncology-Pathology, Karolinska InstitutetDepartment of Oncology-Pathology, Karolinska InstitutetDepartment of Oncology-Pathology, Karolinska InstitutetDepartment of Oncology-Pathology, Karolinska InstitutetDepartment of Oncology-Pathology, Karolinska InstitutetAbstract Background Mesenchymal stromal cells belong to a diverse collection of cells in different states that are poorly characterized in soft-tissue sarcomas. In this study, we explored tumor growth-regulatory signaling between differentially educated non-malignant mesenchymal stromal cells and malignant cells in pediatric rhabdomyosarcoma (RMS). Methods Xenograft experiments demonstrated that non-malignant stromal cells influence tumor behavior. Gene expression analysis identified deregulated genes, which were further studied using cell culture assays and patient data. Clinicopathological correlations were made in a discovery cohort (N = 147) and a validation cohort (N = 101). Results The results revealed transiently suppressive paracrine effects of orthotopic stromal cells derived from skeletal muscle. These effects were lost when the stromal cells were exposed to RMS cells, either short-term in vitro, or long-term in hindlimb muscle in vivo. High resolution microarray-based Clariom D gene expression analysis identified insulin-like growth factor binding protein 5 (IGFBP5) as the top upregulated gene in RMS cells exposed to naïve stromal cells, and effects on growth arrest, caspase 3/7 activation, and myogenic cell identity were demonstrated in functional assays. Furthermore, IGFBP5 associated with the caspase 3 substrate growth arrest specific protein 2 (GAS2), lower disease stage and favorable survival in patient cohorts. Conclusions This study uses functional modeling and omics approaches to identify IGFBP5 as a candidate mediator of anti-tumor growth mechanisms originating from tumor-neighboring mesenchymal stromal cells. Tumors of mesenchymal origin, such as RMS, are known for their heterogeneity, and this could potentially pose a limitation to the study. However, a clinical relevance is emphasized by consistent findings across patient cohorts. These insights pave the way for novel therapeutic strategies modulating activities of stromal cell subsets at primary and metastatic sites in RMS. Graphical Abstracthttps://doi.org/10.1186/s12964-025-02171-6RhabdomyosarcomaMesenchymal stromal cellsIGFBP5ApoptosisGrowth arrest |
| spellingShingle | Yue Zhang Karim Katkhada Liu Zhen Meng Binbin Zhao Shanlin Tong Wiem Chaabane Aditi Kallai Nicholas P. Tobin Arne Östman Alessandro Mega Monika Ehnman Myogenic IGFBP5 levels in rhabdomyosarcoma are nourished by mesenchymal stromal cells and regulate growth arrest and apoptosis Cell Communication and Signaling Rhabdomyosarcoma Mesenchymal stromal cells IGFBP5 Apoptosis Growth arrest |
| title | Myogenic IGFBP5 levels in rhabdomyosarcoma are nourished by mesenchymal stromal cells and regulate growth arrest and apoptosis |
| title_full | Myogenic IGFBP5 levels in rhabdomyosarcoma are nourished by mesenchymal stromal cells and regulate growth arrest and apoptosis |
| title_fullStr | Myogenic IGFBP5 levels in rhabdomyosarcoma are nourished by mesenchymal stromal cells and regulate growth arrest and apoptosis |
| title_full_unstemmed | Myogenic IGFBP5 levels in rhabdomyosarcoma are nourished by mesenchymal stromal cells and regulate growth arrest and apoptosis |
| title_short | Myogenic IGFBP5 levels in rhabdomyosarcoma are nourished by mesenchymal stromal cells and regulate growth arrest and apoptosis |
| title_sort | myogenic igfbp5 levels in rhabdomyosarcoma are nourished by mesenchymal stromal cells and regulate growth arrest and apoptosis |
| topic | Rhabdomyosarcoma Mesenchymal stromal cells IGFBP5 Apoptosis Growth arrest |
| url | https://doi.org/10.1186/s12964-025-02171-6 |
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