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Aldehyde Dehydrogenase, a Therapeutic Target in Chordoma: Analysis in 3D Cellular Models
Marie-Anaïs Locquet1, Anne-Lise Dechaume1, Paul Berchard1
1Team Cell Death and Pediatric Cancer, Cancer Initiation and Tumor Cell Identity Department, INSERM1052, CNRS5286, Cancer Research Center of Lyon, F-69008 Lyon, France.
Abstract:
Chordomas are rare, slow-growing tumors of the axial skeleton. These tumors are locally aggressive and refractory to conventional therapies. Radical surgery and radiation remain the first-line treatments. Despite these aggressive treatments, chordomas often recur and second-line treatment options are limited. The mechanisms underlying chordoma radioresistance remain unknown, although several radioresistant cancer cells have been shown to respond favorably to aldehyde dehydrogenase (ALDH) inhibition. The study of chordoma has been delayed by small patient cohorts and few available models due to the scarcity of these tumors. We thus created cellular 3D models of chordoma by using low-adherence culture systems. Then, we evaluated their radiosensitivity using colony-forming and spheroid size assays. Finally, we determined whether pharmacologically inhibiting ALDH increased their radiosensitivity. We found that 3D cellular models of chordoma (derived from primary, relapse, and metastatic tumors) reproduce the histological and gene expression features of the disease. The metastatic, relapse, and primary spheroids displayed high, medium, and low radioresistance, respectively. Moreover, inhibiting ALDH decreased the radioresistance in all three models.
Insights
Chordoma (a rare bone cancer) spheroids showed varying radioresistance. Aldehyde dehydrogenase (ALDH) inhibition decreased radioresistance in all models, offering a potential new therapeutic strategy for chordoma.
Area of Science:
- Oncology
- Cancer Biology
- Tumor Microenvironment
Background:
- Chordomas are rare, slow-growing, locally aggressive axial skeleton tumors.
- They are refractory to conventional therapies, with limited second-line treatment options.
- Chordoma radioresistance mechanisms are unknown, but aldehyde dehydrogenase (ALDH) inhibition shows promise in other cancers.
Purpose of the Study:
- To develop and characterize 3D cellular models of chordoma.
- To evaluate the radiosensitivity of these chordoma models.
- To determine if ALDH inhibition can enhance chordoma radiosensitivity.
Main Methods:
- Chordoma cells were cultured in low-adherence systems to create 3D spheroids.
- Radiosensitivity was assessed using colony-forming and spheroid size assays.
- The effect of pharmacologic ALDH inhibition on radiosensitivity was evaluated.
Main Results:
- 3D chordoma models recapitulated disease histology and gene expression.
- Metastatic, relapse, and primary chordoma spheroids exhibited high, medium, and low radioresistance, respectively.
- ALDH inhibition reduced radioresistance across all tested chordoma models.
Conclusions:
- 3D chordoma models are valuable tools for studying chordoma biology and treatment resistance.
- Chordoma exhibits differential radioresistance based on tumor origin (primary, relapse, metastatic).
- Targeting ALDH presents a promising strategy to overcome chordoma radioresistance.
