Targeting metastasis in paediatric bone sarcomas

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.

Keywords: Bone; Ewing sarcoma; Metastasis; Osteosarcoma; Sarcoma.

Fig. 1

Metastasis is the defining and fatal feature of cancer. Some primary tumour cells, through multiple mechanisms, invade the local vasculature and spread around the body using the blood circulatory system. In some cases, this could also be the lymphatic system. These so-called circulating tumour cells survive circulatory cytotoxicity, avoid immune detection and invade distant sites to propagate secondary tumours (metastases). Metastases are often drug resistant and generate at inoperable sites meaning their growth and further spread involves the dysfunction of multiple interconnected systems within the body, ultimately leading to patient death. Clinical observations indicate that some primary tumours show a proclivity towards specific distant sites. For example, melanomas tend to spread to the brain. Breast cancers spread to the bones, etc. As depicted, bone sarcomas tend to spread to the lungs

Fig. 2

Post-surgical metastatic relapse following primary tumour resection and potential mechanisms of action

Fig. 3

Panoramic overview of bone sarcoma multi-step metastasis and targets for anti-metastasis medicines. At the top of the figure, the schematic portrays the predicted scenario where the bone sarcoma cell of origin arises during, and arrests in, development caused by rare mutations in specific cell populations during restricted developmental windows. This precursor cell may require secondary activation, for example, hormone onset at adolescence, before mono- or polyclonal expansion and invasion into local tissues. The bottom left of the figure depicts the established primary bone tumour with the multitude of other interacting cells, molecules and genes associated with metastatic propensity, and all potential targets for new therapies. The figure shows CTC escape and into the local blood vasculature where there are reported ion differences between patients with and without metastatic disease as well as increased platelets. The bottom right of the figure displays the PMN, typically the lungs, where new cell types, EVs and genes have been associated with the arrest and propagation of CTCs. Finally, these disseminated cells form secondary tumours, that may themselves shed CTCs enabling metastases-to-metastases dissemination

Fig. 4

Macrophages have been classically defined as M1 and M2 with M2 further categorised into subtypes. TAM heterogeneity blurs these divisions but generally lead to the predominant pro-tumour survival features of M2 phenotypes. scRNA-seq has enabled newer TAM subtypes to be identified and in osteosarcoma, three are displayed here. Signature genes for each subtype are in red