Targeting mTOR Pathway in PTEN Deleted Newly Isolated Chordoma Cell Line

Chordomas are rare primary malignant tumours of notochordal origin usually arising along the axial skeleton with particular predilection of the skull base and sacrococcygeal region. Albeit usually slow-growing, chordomas can be aggressive mostly depending on their invasive behaviour and according to different histotypes and molecular alterations, including TBXT duplication and SMARCB1 homozygous deletion. Partial or complete PTEN deficiency has also been observed. PTEN is a negative regulator of the Akt/mTOR pathway and hyperactivation of Akt/mTOR in cells lacking PTEN expression contributes to cell proliferation and invasiveness. This pathway is targeted by mTOR inhibitors and the availability of in vitro models of chordoma cells will aid in further investigating this issue. However, isolation and maintenance of chordoma cell lines are challenging and PTEN-deleted chordoma cell lines are exceedingly rare. Hereby, we established and characterized a novel human PTEN-deleted chordoma cell line (CH3) from a primary skull base chordoma. Cells exhibited morphological and molecular features of the parent tumour, including PTEN loss and expression of Brachyury and EMA. Moreover, we investigated the activation of the mTOR pathway and cell response to mTOR inhibitors. CH3 cells were sensitive to Rapamycin treatment suggesting that mTOR inhibitors may represent a valuable option for patients suffering from PTEN-deleted chordomas.

Automated summary

Chordomas are rare primary malignant tumors arising from the notochord, with a propensity for the skull base and sacrococcygeal region. Different histotypes and molecular alterations, including PTEN deficiency, contribute to the aggressiveness of chordomas. PTEN loss leads to hyperactivation of the Akt/mTOR pathway, which promotes cell proliferation and invasiveness. In this study, a new human PTEN-deleted chordoma cell line was established and characterized, exhibiting molecular features similar to the parent tumor. These cells were sensitive to treatment with mTOR inhibitors, suggesting their potential therapeutic value for PTEN-deleted chordoma patients.