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Aberrant paracrine signalling for bone remodelling underlies the mutant histone-driven giant cell tumour of bone

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Lucia Cottone, Lorena Ligammari, Hang Mao Lee, Helen J. Knowles, Stephen Henderson, Sara Bianco, Christopher Davies, Sandra Strauss, Fernanda Amary, Ana Paula Leite, Roberto Tirabosco, Kristian Haendler, Joachim L. Schultze, Javier Herrero, Paul O’Donnell, Agamemnon E. Grigoriadis, Paolo Salomoni, Adrienne M. Flanagan

Original languageEnglish
Pages (from-to)2459-2471
Number of pages13
JournalCELL DEATH AND DIFFERENTIATION
Volume29
Issue number12
DOIs
Accepted/In press2022
PublishedDec 2022

Bibliographical note

Funding Information: Funding for this project was received from the UK Medical Research Council grant (MR/M00094X/1) (AMF and PS), PRECISE platform (PS), The Tom Prince Cancer Trust (AMF), Skeletal Action Trust UK (AMF), the Royal National Orthopaedic Hospital NHS Trust R&D Department, the Rosetrees and Stoneygate Trusts (M46-F1) (AMF), the Bone Cancer Research Trust Infrastructure grant (AMF), and the Brain Tumour Charity (PS). AMF, LC, PS and AL were supported by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre, and the Cancer Research UK University College London Experimental Cancer Medicine Centre. LC was supported by The Tom Prince Cancer Trust. PS was supported by the Cancer ERC Consolidator award until May 2019 and is currently supported by a project grant on histone variants from the Wilhelm Sander Stiftung, by the DFG under Germany’s Excellence Strategy (Grant no. EXC2151–390873048; Excellence Cluster ImmunoSensation2) and the Helmholtz-Gemeinschaft Aging and Metabolic Programming (AMPro) Consortium, along with other funding bodies. PS is a member of the Bonn International Graduate School of Neuroscience. HK is funded by Arthritis Research UK (MP/19200) and Rosetrees Trust (M456). SH was funded by the Cancer Research UK-University College London (CRUK-UCL) Centre Award [C416/A25145]. This work was also supported by the UCL Cancer Institute Flow Cytometry Facility, funded by the CRUK-UCL Centre Award (Grant no. C416/A25145) and the CRUK Cancer Immunotherapy Network Accelerator (CITA) Award (grant no. C33499/A20265) as well as CRUK Centre award to Barts Cancer Centre (Grant no. C16420/A18066) and the UCL Biomedical Research Centre. Funding Information: We thank Diana Carvalho, UCL, for her contribution to preliminary experiments; Francesco Saverio Tedesco, UCL, for providing the iPSC cells; Teresa Sposito for help with iPSC cultures; Manuel Rodriguez Justo and Dominic Patel, UCL, for support with digital images; Ivana Bjedov, UCL, for providing S2 cells; Jenny Russ, Manon Chevallot-Beroux and PS other lab members for advice and support in particular with respect to NGS-related work. We also thank the Daniele Bano and Pierluigi Nicotera teams (DZNE Bonn) for support. We thank the DZNE Core Facilities, Platform foR SinglE Cell GenomIcS and Epigenomics (PRECISE, DZNE Bonn), the Biobank Team and the Research and Development Department at the RNOH, the healthcare workers and the patients for the generous donation of their material. Publisher Copyright: © 2022, The Author(s).

King's Authors

Abstract

Oncohistones represent compelling evidence for a causative role of epigenetic perturbations in cancer. Giant cell tumours of bone (GCTs) are characterised by a mutated histone H3.3 as the sole genetic driver present in bone-forming osteoprogenitor cells but absent from abnormally large bone-resorbing osteoclasts which represent the hallmark of these neoplasms. While these striking features imply a pathogenic interaction between mesenchymal and myelomonocytic lineages during GCT development, the underlying mechanisms remain unknown. We show that the changes in the transcriptome and epigenome in the mesenchymal cells caused by the H3.3-G34W mutation contribute to increase osteoclast recruitment in part via reduced expression of the TGFβ-like soluble factor, SCUBE3. Transcriptional changes in SCUBE3 are associated with altered histone marks and H3.3G34W enrichment at its enhancer regions. In turn, osteoclasts secrete unregulated amounts of SEMA4D which enhances proliferation of mutated osteoprogenitors arresting their maturation. These findings provide a mechanism by which GCTs undergo differentiation in response to denosumab, a drug that depletes the tumour of osteoclasts. In contrast, hTERT alterations, commonly found in malignant GCT, result in the histone-mutated neoplastic cells being independent of osteoclasts for their proliferation, predicting unresponsiveness to denosumab. We provide a mechanism for the initiation of GCT, the basis of which is dysfunctional cross-talk between bone-forming and bone-resorbing cells. The findings highlight the role of tumour/microenvironment bidirectional interactions in tumorigenesis and how this is exploited in the treatment of GCT.

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