Cancer-associated fibroblast heterogeneity in chordoma†

Abstract

In solid tumours, malignant cells develop relationships with nonmalignant stromal cells to support tumour growth, tissue structure, and nutrient supply. In a recent issue of this journal, Zheng and Guo catalogue the cellular landscape in chordoma using a combination of single-cell and spatial transcriptomics. Despite the mesenchymal nature of chordoma, malignant cells retain expression of epithelial markers, in addition to mesenchymal, partial-EMT, and stem-cell signatures. Cancer-associated fibroblasts (CAFs) are among the most abundant stromal cells and the authors define an inflammatory CAF subtype (iCAF), which is associated with poor outcome and tumour invasion. It is proposed that iCAFs arise from normal fibroblasts during malignant tumour progression and play a causative role in driving an invasive poor prognosis tumour phenotype. Recent reports by this and other groups have separately catalogued cell populations, including CAFs and immune cells in chordoma. The next challenge will be to integrate findings from these distinct studies to allow a consensus to be reached regarding cellular heterogeneity within chordoma, and to allow comparison of CAF populations with those found in other tumour types. Comparison of CAF functions in these predominantly mesenchymal tumours with epithelial solid tumours may reveal interesting lessons about the diverse phenotypes CAFs can bring to distinct tumour ecosystems. Understanding the role of CAFs in chordoma progression may also lead to therapeutic opportunities, but separation of correlation and causation in CAF regulation of tumour phenotypes remains a significant challenge. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: cancer‐associated fibroblasts; chordoma; single‐cell transcriptomics; spatial transcriptomics; tumour invasion.

Figure 1

Distinct CAF subtypes arising in chordoma. Endoplasmic reticulum stress (ERS) and energy metabolism CAFs are localised in close association with chordoma tumour cells, in contrast to inflammatory iCAFs, which are not found in close proximity [2, 3]. In separate studies, both ERS CAFs and iCAFs are associated with tumour invasion and poor prognosis, albeit with distinct proposed mechanisms. Further, ERS CAFs are almost exclusively found in recurrent chordomas. Created in BioRender; Henry, J. (2025) https://BioRender.com/a94t585.