Development and validation of basement membrane-related signatures for predicting postoperative recurrence, tumor microenvironment and drug candidates in chordomas.

Abstract

Background: Skull base chordoma is a rare and aggressive bone tumor with a poor prognosis. The basement membrane (BM) plays an pivotal role in tumor progression. However, the involvement of BM-related genes in assessing the prognosis and influencing the biological behavior of skull base chordomas remains unclear.

Methods: Patients with skull base chordoma undergoing endoscopic endonasal surgery were included in the study (77 patients for bulk transcriptome sequencing and 6 patients for single-cell RNA sequencing). A BM-related genes signature was established and validated using bulk transcriptome data. Additionally, we investigated the oncogenic potential of a key BM-related gene in chordoma cells in vitro.

Results: A prognostic signature consisting of five BM-related genes was identified through LASSO Cox regression analysis. The accuracy and reliability of this signature were validated by the validation cohort. Multivariate Cox analysis and a nomogram demonstrated that the risk score serves as an independent and reliable prognostic factor for skull base chordoma. Moreover, the BM-related gene signature was significantly associated with the immune microenvironment, immune checkpoint expression, and drug sensitivity. Single-cell RNA sequencing analysis revealed both the chordoma tumor cell and the fibroblast contributed to the overall BM signature. Finally, in vitro experiments demonstrated that the knockdown of ITGB3, the hub gene in the signature, inhibited the proliferation and migration of chordoma cells via the PI3K-Akt pathway.

Conclusion: This study explored the critical role of BM-related genes in skull base chordoma, which affected postoperative recurrence and maligant behavior of chordoma via the PI3K-Akt signaling pathway.