Development and Characterization of a Primary Patient Tumor Tissue-Derived Skull-Base Chordoma Organoid Model

Skull-base chordoma (SBC) is a rare and locally aggressive primary bone malignancy that arises from embryonic remnants of the notochord, typically near the midline at the sellar or clivus regions. SBC has a high recurrence rate despite the standard of care involving maximal surgical resection and adjuvant radiotherapy, likely due to its complex anatomical location and locally invasive nature. Therapeutic options for SBCs remain limited, partly due to the lack of reliable preclinical models that resemble its complexity. To address this critical gap, we developed an organoid model that recapitulates SBC tumor features in culture and allows for the investigation of novel therapeutics. We generated three-dimensional (3D) skull-base chordoma organoids (SBCOs) by dissecting resected patient tumors and culturing them in a chemically defined medium on an orbital shaker. SBCOs were successfully generated from all seven patients within 2 to 3 weeks postsurgery ([Fig. 1]). Comparison with the parental tumor showed that SBCOs faithfully preserved the histomorphological and immunohistochemical features of primary tumors, including the expression of TBXT (Brachyury), a transcription factor recently identified as a selective dependency in SBC ([Figs. 2] and [3]). The SBCOs also retained proliferative tumor cells indicated by the expression of Ki67 and SOX9, and preserved elements of the tumor microenvironment ([Fig. 3]). Current efforts are focused on establishing the timeline of genetic and transcriptomic concordance between SBCOs and primary tissue, as well as evaluating their ex vivo responses to a panel of small-molecule inhibitors and genetic perturbations. Together, this SBCO model represents a novel and valuable platform for studying the underlying biology of SBC and for screening novel therapeutic approaches.

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Artikel online veröffentlicht:
07. Februar 2025