New insights into osteosarcoma metastasis
GTSE1 and CREB3L1 promote a pro-metastatic tumor microenvironment in osteosarcoma
image: (A) t-SNE visualization of major cell lineages. (B) The dot plots showing the average expression of 22 signature genes across the 10 cellular clusters. The dot sizes indicated the proportions of cells expressing the genes in each cluster and the color spectrum represented the mean expression levels of the signature genes. (C) Relative proportions of 10 clusters across primary and metastatic tissues as indicated. (D–F) t-SNE visualization of OB cell subsets (D), CB cell subsets (E), and OC cell subsets (F). (G–I) The dot plots showing the average expression of selected signature genes in OB cell subsets (G), CB cell subsets (H), and OC cell subsets (I). The dot sizes indicated the proportions of cells expressing the genes in each subset and the color spectrum represented the mean expression levels of the markers. (J, K) The dot plots showing the average expression of selected signature genes in myeloid cell subsets (J), and tumor-infiltrating lymphocyte subsets (K). (L, M) Dot plots showing average expression of selected signature genes in myeloid cell subsets (L), and tumor-infiltrating lymphocyte subsets (M). The dot sizes indicated the proportions of cells expressing the genes in each subset and the color spectrum represented the mean expression levels of the markers.
Credit: Linzhu Wang, Wenyue Li, Weihang Ji, Danyang Bing, Mingyue Liu, Kaidong Liu, Bo Chen, Zhangxiang Zhao, Yunyan Gu, Xuelian Li, Xiaoqiang E, Lei Yang
Osteosarcoma (OS) is a malignant bone tumor with a poor prognosis. Metastasis reduces the long-term survival of OS patients, with a five-year survival rate of less than 20%. Delineating the underlying cellular and molecular diversity may help in understanding the progression from primary to metastatic OS.
In a recent study published in the Genes & Diseases journal, researchers at the Harbin Medical University and Chongqing University analyzed single-cell and bulk gene expression datasets from primary and metastatic samples to map the OS cell atlas.
An scRNA-seq dataset comprising seven primary OS samples and two metastatic OS samples revealed that the metastatic samples were enriched in osteoblasts (OB) and tumor-infiltrating lymphocytes, with fewer myeloid cells and osteoclasts (OC) than primary samples, suggesting intertumoral heterogeneity among lesions.
Additionally, the authors observed an increase in the GTSE1+ OB and CREB3L1+ chondroblasts (CB) populations in metastatic OS and showed that the GTSE1+ OB cells, monocytes, CD8+ T cells, CREB3L1+ CB, and fibroblasts jointly contribute to the formation of a pro-metastatic tumor niche. Furthermore, the GSTE1+ OB cells displayed high proliferative ability, as evidenced by the increased expression of genes involved in cell division and DNA repair pathways, and the distribution of these cells in the G2, M, or S phase of the cell cycle.
Overexpression of GTSE1 in OB cells was associated with poor survival, stemness, invasion, and metastasis, while its knockdown suppressed the growth, migration, and invasion of OB cells, highlighting the pivotal role of GTSE1 in regulating OS metastasis. GSTE1+ OB cells evade CD8+ T cell-mediated killing via preferentially interacting with MIF-(CD74-CXCR4).
Similarly, high CREB3L1 expression in CB cells was associated with poor overall survival, poor prognosis, and metastasis. The CREB3L1+ CB cells interact with fibroblasts and regulate extracellular matrix remodelling and inflammatory responses, to create a pro-metastatic tumor microenvironment that facilitates cancer cell growth and metastasis.
In conclusion, the results of this study show that the GTSE1+ OB and CREB3L1+ CB cell populations are enriched in the metastatic niche of OA. It also provides insights into how increased expression of GTSE1 in OB cells and CREB3L1 in CB cells contribute to a pro-metastatic niche that drives OS progression and metastasis.
Reference
Title of the original paper: GTSE1-expressed osteoblastic cells facilitate formation of pro-metastatic tumor microenvironment in osteosarcoma
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101591
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