Targeting mTOR Pathway in PTEN Deleted Newly Isolated Chordoma Cell Line

Abstract

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.

Immunomodulation exerted by galectins: a land of opportunity in rare cancers

“…One such pathway is that of mTOR, which is frequently hyperactivated in chordomas and has been suggested as a possible therapeutic target (95,96). This emanates from the fact that a partial or complete Phosphatase and Tensin Homolog (PTEN) deficiency generates hyperactivation of the Akt/mTOR pathway, therefore PTEN is a negative regulator of this pathway, and its absence contributes to chordoma development (97).…”

“…The CH3 cell line is derived from a primary skull base chordoma with both conventional and chondroid features. These cells do not express PTEN, which contributes to cell proliferation and invasiveness (97). Aside from its effects on the activation of the Akt/mTOR pathway (97), the partial or complete PTEN deficiency potentially induces the secretion of Gal-9 (99), as it does in glioblastoma cells via the AKT-GSK-3b-IRF1 pathway.…”