Aberrant paracrine signalling underlies oncohistone-driven giant cell tumour of bone [ChIP-seq]

ABSTRACT: The identification of oncohistones underscores the neoplasm-driving role of chromatin dysfunction. However, we have limited understanding of how these perturbations alter communication in the tumour microenvironment (TME) and the functional implications of this crosstalk. In this respect, clinical evidence shows that the maturation block of the H3F3A (H3.3G34W)-mutated osteoblastic stromal population in benign giant cell tumours (GCTs), a neoplasm characterised by a prominent mutation-free osteoclast component, is reversed on osteoclast depletion, suggesting aberrant interactions between these two cell populations. Here, we reveal a bidirectional paracrine mechanism at the root of oncohistone-driven neoplasia in this bone tumour. H3.3G34W fails to induce stromal cell proliferation but inhibits their maturation. Altered chromatin landscape of these cells leads to enhancer remodelling, including at SCUBE3, a Tgfbeta family member. Reduced SCUBE3 expression contributes to increased osteoclasts that secrete high levels of SEMA4D, which disproportionately blocks maturation of H3.3G34W-expressing cells. Together, our findings suggest that non-cell autonomous provision of a growth advantage to a cancer driver-bearing cell represents a paradigm for a benign neoplasm.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152921 | GEO | 2022/08/05

REPOSITORIES: GEO