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Publications

Journal Article Review Epublish

PubMed: 40442778 DOI: 10.1186/s12943-025-02365-z

Targeting metastasis in paediatric bone sarcomas.

Mol Cancer 24(1):153

Authors: Emma C Bull, Archana Singh, Amy M Harden, Kirsty Soanes, Hala Habash, Lisa Toracchio, Marianna Carrabotta, Christina Schreck, Karan M Shah, Paulina Velasco Riestra, Margaux Chantoiseau, Maria Eugénia Marques Da Costa, Gaël Moquin-Beaudry, Pan Pantziarka, Edidiong Akanimo Essiet, Craig Gerrand, Alison Gartland, Linda Bojmar, Anna Fahlgren, Antonin Marchais, Evgenia Papakonstantinou, Eleni M Tomazou, Didier Surdez, Dominique Heymann, Florencia Cidre-Aranaz, Olivia Fromigue, Darren W Sexton, Nikolas Herold, Thomas G P Grünewald, Katia Scotlandi, Michaela Nathrath, Darrell Green

Affiliations

  • Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK.
  • Amity Institute of Biotechnology, Amity Institute of Integrative Sciences and Health, Amity University Haryana, Gurugram, India.
  • Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  • Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
  • Children's Cancer Research Center, Klinikum Rechts Der Isar, Technical University of Munich, Munich, Germany.
  • School of Medicine and Population Health, The University of Sheffield, Sheffield, UK.
  • Biomedical and Clinical Sciences, Division of Surgery, Orthopaedics and Oncology, Linköping University, Linköping, Sweden.
  • Gustave Roussy Institute, Villejuif, France.
  • Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
  • Anticancer Fund, Meise, Belgium.
  • The George Pantziarka TP53 Trust, London, UK.
  • Orthopaedic Oncology, Royal National Orthopaedic Hospital, Stanmore, UK.
  • Biomedical and Clinical Sciences, Division of Cell and Neurobiology, Linköping University, Linköping, Sweden.
  • Pediatric Hematology-Oncology, Ippokratio General Hospital of Thessaloniki, Thessaloniki, Greece.
  • St. Anna Children's Cancer Research Institute, Vienna, Austria.
  • Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
  • Faculty of Medicine, Balgrist University Hospital, University of Zurich, Zurich, Switzerland.
  • UMR6286, Nantes Université, CNRS, US2B, Nantes, France.
  • Institut de Cancérologie de L'Ouest, Saint-Herblain, France.
  • Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  • German Cancer Research Center (DKFZ), Division of Translational Pediatric Sarcoma Research, German Cancer Consortium (DKTK), Heidelberg, Germany.
  • National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
  • Inserm UMR981, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France.
  • School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK.
  • Paediatric Oncology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
  • Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Pediatric Oncology, Klinikum Kassel, Kassel, Germany.
  • Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK.

Abstract

Paediatric bone sarcomas (e.g. Ewing sarcoma, osteosarcoma) comprise significant biological and clinical heterogeneity. This extreme heterogeneity affects response to systemic therapy, facilitates inherent and acquired drug resistance and possibly underpins the origins of metastatic disease, a key component implicit in cancer related death. Across all cancers, metastatic models have offered competing accounts on when dissemination occurs, either early or late during tumorigenesis, whether metastases at different foci arise independently and directly from the primary tumour or give rise to each other, i.e. metastases-to-metastases dissemination, and whether cell exchange occurs between synchronously growing lesions. Although it is probable that all the above mechanisms can lead to metastatic disease, clinical observations indicate that distinct modes of metastasis might predominate in different cancers. Around 70% of patients with bone sarcoma experience metastasis during their disease course but the fundamental molecular and cell mechanisms underlying spread are equivocal. Newer therapies such as tyrosine kinase inhibitors have shown promise in reducing metastatic relapse in trials, nonetheless, not all patients respond and 5-year overall survival remains at ~ 50%. Better understanding of potential bone sarcoma biological subgroups, the role of the tumour immune microenvironment, factors that promote metastasis and clinical biomarkers of prognosis and drug response are required to make progress. In this review, we provide a comprehensive overview of the approaches to manage paediatric patients with metastatic Ewing sarcoma and osteosarcoma. We describe the molecular basis of the tumour immune microenvironment, cell plasticity, circulating tumour cells and the development of the pre-metastatic niche, all required for successful distant colonisation. Finally, we discuss ongoing and upcoming patient clinical trials, biomarkers and gene regulatory networks amenable to the development of anti-metastasis medicines.

MeSH

Cells, Genes, Pharmaceutical Preparations, Neoplasms, Biomarkers, Sarcoma, Neoplasm Metastasis, Therapeutics, Osteosarcoma

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