Chordomas are rare, slowly growing, locally aggressive bone neoplasms that arise from embryonic remnants of the notochord, showing dual epithelial-mesenchymal differentiation. The high plasticity probably is the main reason for the high variety in phenotypes of chordoma, from its high heterogeneity on a cellular level to its subtype variations depending on tissue location, with its potential to develop from an inactive quiescent form to an aggressive cancer with extreme adaptability and resistance to drugs and other treatments. Gene expression profiles of formalin-fixed, paraffin-embedded skull chordoma, spine chordoma, and normal tissue specimens were generated and compared. Using strict criteria, we identified 222 differentially expressed transcripts unique to skull base chordoma, 261 unique to spine chordoma, and 192 common to both chordoma subtypes. Further analysis of these three groups of transcripts allowed the selection of three subsets of highly differentially expressed genes as potential biomarkers, disease drivers, and therapeutic targets in both chordoma subtypes. Immunohistochemistry revealed LMX1A to be dominant in skull base chordoma, SALL3 to be unique to spine chordoma, and T to be common to both chordoma subtypes. In both chordoma subtypes, the genes with the highest expression were predominantly development-related genes, mostly transcription factors. Our findings indicate that these developmental genes play important oncogenic roles in chordoma, mainly causing high plasticity and resistance to therapy in both these cancer subtypes but also determining their differentiation status and proliferation activity, pointing to features expected of heterogeneous stem cell-like tissues with similarities to their notochord origins.
Chordoma Skull base Spine Transcriptome Developmental genes Stem cells Plasticity
This is a preview of subscription content, log in to check access.
This study was supported by start-up funds from MD Anderson (DB) and presented at AACR Advances in Sarcoma, Philadelphia May 2017.
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Conflict of interest
The authors declare that they have no conflict of interest.
Bell D, Bell AH, Bondaruk J, Hanna EY, Weber RS (2016) In-depth characterization of the salivary adenoid cystic carcinoma transcriptome with emphasis on dominant cell type. CancerGoogle Scholar
Faial T, Bernardo AS, Mendjan S et al (2015) Brachyury and SMAD signalling collaboratively orchestrate distinct mesoderm and endoderm gene regulatory networks in differentiating human embryonic stem cells. Development 142:2121–2135CrossRefPubMedPubMedCentralGoogle Scholar
Chao TK, Yo YT, Liao YP et al (2013) LIM-homeobox transcription factor 1, alpha (LMX1A) inhibits tumourigenesis, epithelial-mesenchymal transition and stem-like properties of epithelial ovarian cancer. Gynecol Oncol 128:475–482CrossRefPubMedGoogle Scholar
Yagi K, Satou Y, Satoh N (2004) A zinc finger transcription factor, ZicL, is a direct activator of Brachyury in the notochord specification of Ciona intestinalis. Development 131:1279–1288CrossRefPubMedGoogle Scholar
Heng X, Breer H, Zhang X et al (2012) Sall3 correlates with the expression of TH in mouse olfactory bulb. J Mol Neurosci 46:293–302CrossRefPubMedGoogle Scholar
Lin CC, Hsu YC, Li YH et al (2017) Higher HOPX expression is associated with distinct clinical and biological features and predicts poor prognosis in de novo acute myeloid leukemia. Haematologica 102:1044–1053CrossRefPubMedPubMedCentralGoogle Scholar
Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo HW (2016) Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers (Basel) 8Google Scholar
Corradetti MN, Inoki K, Guan KL (2005) The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. J Biol Chem 280:9769–9772CrossRefPubMedGoogle Scholar
Morquette B, Morquette P, Agostinone J et al (2015) REDD2-mediated inhibition of mTOR promotes dendrite retraction induced by axonal injury. Cell Death Differ 22:612–625CrossRefPubMedGoogle Scholar
Yang YF, Pan YH, Cao Y et al (2017) PDZ binding kinase, regulated by FoxM1, enhances malignant phenotype via activation of beta-catenin signaling in hepatocellular carcinoma. OncotargetGoogle Scholar
Li Q, Qi X, Jia W (2016) 3,3′,5-triiodothyroxine inhibits apoptosis and oxidative stress by the PKM2/PKM1 ratio during oxygen-glucose deprivation/reperfusion AC16 and HCM-a cells: T3 inhibits apoptosis and oxidative stress by PKM2/PKM1 ratio. Biochem Biophys Res Commun 475:51–56CrossRefPubMedGoogle Scholar
Lorenzi L, Doring C, Rausch T et al (2017) Identification of novel follicular dendritic cell sarcoma markers, FDCSP and SRGN, by whole transcriptome sequencing. Oncotarget 8:16463–16472CrossRefPubMedPubMedCentralGoogle Scholar
Liu H, Zhang X, Wu J, French SW, He Z (2016) New insights on the palate, lung, and nasal epithelium clone (PLUNC) proteins: based on molecular and functional analysis of its homolog of YH1/SPLUNC1. Exp Mol Pathol 100:363–369CrossRefPubMedGoogle Scholar
Ma Z, Li M, Roy S et al (2016) Chromatin boundary elements organize genomic architecture and developmental gene regulation in Drosophila Hox clusters. World J Biol Chem 7:223–230CrossRefPubMedPubMedCentralGoogle Scholar
Rhie SK, Guo Y, Tak YG et al (2016) Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits. Epigenetics Chromatin 9:50CrossRefPubMedPubMedCentralGoogle Scholar
Moorthy SD, Davidson S, Shchuka VM et al (2017) Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes. Genome Res 27:246–258CrossRefPubMedPubMedCentralGoogle Scholar
Mangum R, Varga E, Boue DR et al (2016) SHH desmoplastic/nodular medulloblastoma and Gorlin syndrome in the setting of Down syndrome: case report, molecular profiling, and review of the literature. Childs Nerv Syst 32:2439–2446CrossRefPubMedGoogle Scholar