Metastasis-initiating osteosarcoma subpopulations establish paracrine interactions with both lung and tumor cells to create a metastatic niche
Metastasis-initiating osteosarcoma subpopulations establish paracrine interactions with both lung and tumor cells to create a metastatic niche
ABSTRACT Osteosarcoma is an aggressive and deadly bone tumor, primarily afflicting children, adolescents, and young adults. Poor outcomes for osteosarcoma patients are intricately linked with the development of lung metastasis. While lung metastasis is responsible for nearly all deaths caused by osteosarcoma, identification of biologically defined, metastasis-targeting therapies remains elusive because the underlying cellular and molecular mechanisms that govern metastatic colonization of circulating tumor cells to the lung remains poorly understood. While thousands of tumor cells are released into circulation each day, very few can colonize the lung. Herein, using a combination of a novel organotypic metastasis in vitro model, single-cell RNA sequencing, human xenograft, and murine immunocompetent osteosarcoma models, we find that metastasis is initiated by a subpopulation of hypo-proliferative cells with the unique capacity to sustain production of metastasis promoting cytokines such as IL6 and CXCL8 in response to lung-epithelial derived IL1α. Critically, genomic and pharmacologic disruption of IL1 signaling in osteosarcoma cells significantly reduces metastatic progression. Collectively, our study supports that tumor-stromal interactions are important for metastasis, and suggests that metastatic competency is driven, in part, by the tumor cell’s ability to respond to the metastatic niche. Our findings support that disruption of tumor-stromal signaling is a promising therapeutic approach to disrupt metastasis progression.
Cannon Matthew V.、Dries Ruben、Hinckley John、Garcia Leyre Jimenez、Cam Maren、Roberts Ryan D.、Gross Amy C.、Gryder Berkley E.、Saraf Amanda、Pommellette Helene Le、Reinecke James B.、Vatelle Sophia
Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children?ˉs HospitalSection of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center||Division of Computational Biomedicine, Boston University School of MedicineBattelleCenter for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children?ˉs Hospital||Molecular, Cellular, and Developmental Biology Program, The Ohio State UniversityInstitute for Genomic Medicine, Nationwide Children?ˉs HospitalCenter for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children?ˉs Hospital||Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children?ˉs Hospital||The Ohio State University James Comprehensive Cancer CenterCenter for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children?ˉs HospitalDepartment of Genetics and Genome Sciences, Case Western Reserve University School of MedicineDepartment of Hematology, Oncology, and Bone Marrow Transplant, Riley Children?ˉs Hospital||Indiana University Department of PediatricsThe Ohio State University College of Veterinary MedicineCenter for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children?ˉs Hospital||Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children?ˉs HospitalCenter for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children?ˉs Hospital
肿瘤学基础医学分子生物学
Cannon Matthew V.,Dries Ruben,Hinckley John,Garcia Leyre Jimenez,Cam Maren,Roberts Ryan D.,Gross Amy C.,Gryder Berkley E.,Saraf Amanda,Pommellette Helene Le,Reinecke James B.,Vatelle Sophia.Metastasis-initiating osteosarcoma subpopulations establish paracrine interactions with both lung and tumor cells to create a metastatic niche[EB/OL].(2025-03-28)[2025-06-07].https://www.biorxiv.org/content/10.1101/2024.06.09.597967.点此复制
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