ESTRO 2024 - Abstract Book

S5270 ESTRO 2024 Pathological Phenotypes and Radiation Sensitivity of Airway Stem Cells Derived from COPD Patients. Radiobiology - Normal tissue radiobiology

Lorena Giuranno, Jolanda Piepers, Evelien Korsten, Dirk De Ruysscher, Marc Vooijs

Maastricht University Medical Centre, Radiation Oncology, Maastricht, Netherlands

Purpose/Objective:

Radiation therapy (RT) is a common treatment for lung cancer, but it can lead to irreversible loss of pulmonary function and a significant reduction in quality of life for one-third of patients. Pre-existing co-morbidities, such as chronic obstructive pulmonary disease (COPD), are frequent in lung cancer patients and further increase the risk of complications. Because lung stem cells are crucial for the regeneration of lung tissue following injury, we hypothesised that airway stem cells from COPD patients with lung cancer may contribute to increased radiation sensitivity.

Material/Methods:

We utilised the Air-Liquid Interface (ALI) model, a three-dimensional (3D) culture system that produces a pseudo stratified mucociliary and polarised lung epithelium from bronchial airway stem cells, to compare the DNA damage response, long and short-term survival and differentiation of primary human airway stem cells from healthy and COPD patients.

Results:

We found that COPD-derived airway stem cells compared to healthy airway stem cell cultures exhibited disproportionate pathological mucociliary differentiation, aberrant cell cycle checkpoints, residual DNA damage, reduced survival of stem cells and self-renewal and terminally differentiated cells post-irradiation, which could be reversed by blocking the Notch pathway using small molecule inhibitors

Conclusion:

Our investigation demonstrates that ex vivo cultured upper airway stem cells derived from individuals with Chronic Obstructive Pulmonary Disease (COPD) faithfully recapitulate key histopathological abnormalities observed in COPD patients. Notably, these cultured COPD stem cells manifest aberrant mucociliary differentiation patterns, heightened sensitivity to irradiation, and first-line tyrosine kinase inhibitors typically employed in treating EGFR-mutated lung cancer. Our study has demonstrated that COPD stem cells exhibit a marked augmentation in radiation-induced DNA damage and diminished viability 24 hours post-irradiation, coupled with compromised long-term survival compared with their healthy airway stem cell counterparts. Furthermore, these COPD stem cells display reduced functionality in the context of non-homologous end-joining DNA repair pathways, which underlies their tendency towards G2-M cell cycle arrest and apoptosis. Of particular significance, our research has unveiled that inhibition of the Notch stem cell signaling pathway can mitigate radiation-induced cell death in COPD stem cells and bolster their survival. Furthermore, the blockade of Notch signaling can reverse the pathological phenotype associated with COPD.