Cholesterol metabolism emerges as a therapeutic target in chordoma

Chordomas are rare primary malignant sarcomas that arise from remnants of the fetal notochord. They are frequently diagnosed at advanced stages, at which point tumors have often invaded adjacent muscle and other critical soft tissues. This local invasiveness makes complete surgical resection difficult and contributes to high rates of recurrence and metastasis.1 Moreover, chordomas are typically resistant to chemotherapy and currently lack approved molecularly targeted therapies.2 A recent study by Zheng et al, published in Neuro-Oncology, reports the discovery and characterization of a novel, therapeutically actionable signaling axis in chordoma.3 Although chordomas are mesenchymal in origin, previous work by the same group has demonstrated that they exhibit epithelial-like features.4,5 Tumor budding (TB)—defined as small clusters of tumor cells within the tumor microenvironment (TME)—is a well-established prognostic marker in many epithelial malignancies.6 In this study, the authors identify tumor budding–like (TBL) structures in chordomas and show that these structures play a central role in tumor biology and may be exploited for targeted therapy development. Analysis of 481 chordoma tissue samples across four independent cohorts revealed widespread presence of TBL structures. A high TBL burden was significantly associated with aggressive clinicopathologic features, including muscle invasion, advanced tumor stage, and reduced overall survival. Using digital spatial profiling (DSP), single-cell RNA sequencing, and differential gene expression analysis of bulk RNA sequencing data, the authors identified a distinct population of tumor budding–like cells (TBLCs) defined by a specific transcriptional signature. Pathway and gene set variation analyses showed that TBLCs were enriched for cancer stem cell–associated programs and exhibited markedly elevated cholesterol metabolism. To determine whether dysregulated cholesterol metabolism contributes to TBLC stemness and malignancy, chordoma cell lines were treated with exogenous cholesterol or cholesterol metabolism inhibitors. Cholesterol supplementation promoted proliferation, migration, invasion, epithelial–mesenchymal transition (EMT), and stemness, while suppressing apoptosis. These pro-tumorigenic effects were recapitulated in chordoma-derived organoid models. Furthermore, implantation of cholesterol-treated organoids into mice resulted in larger and heavier tumors, supporting a role for cholesterol metabolism in ­chordoma progression.