Clinical-proteomic classification and precision treatment strategy of chordoma

Chordoma is a rare and heterogeneous mesenchymal malignancy, with distinct clinical and biological behaviors. Till now, its comprehensive clinical-molecular characteristics and accurate molecular classification remain obscure. In this research, we enroll 102 patients with chordoma and describe their clinical, imageological, and histopathological features. Through tandem mass tag-based proteomic analysis and nonnegative matrix factorization clustering, we classify chordoma into three molecular subtypes: bone microenvironment-dominant, mesenchymal-derived, and mesenchymal-to-epithelial transition-mediated pattern. The three subtypes exhibit discrete clinical prognosis and distinct biological attributes of osteoclastogenesis and immunogenicity, oxidative phosphorylation, and receptor tyrosine kinase activation, suggesting targeted therapeutic strategies of denosumab, S-Gboxin, and anlotinib, respectively. Notably, these approaches demonstrate positive treatment outcomes for each subtype in vitro and in vivo. Altogether, this work sheds light on the clinical-proteomic characteristics of chordoma and provides a candidate precision treatment strategy for chordoma according to molecular classification, underscoring their potential for clinical application. [Display omitted] •The imaging, histopathological, and proteomic landscape of chordoma is constructed•Three molecular subtypes are classified by proteomic analysis of chordoma•Chordoma proteomic subtypes reveal distinct clinical and biological attributes•Three proteomic subtypes exhibit susceptibilities to potential targeted agents Yin et al. provide the proteomic landscape of 102 patients with chordoma and describe the biological characteristics underlying clinical features. The proteomic clustering reveals three molecular subgroups with distinct clinical-biological attributes and therapeutic responses. These findings suggest a precision treatment strategy for chordoma subtypes, highlighting the potential for clinical practice.