Biology subjects

Penninckx, S.

Publications and source records attributed to Penninckx, S..

3 recordsLinked to original sources

bioRxiv2024

APR-246 & COTI-2 increase chemoradiotherapy sensitivity via ROS-induced DNA damage and ferroptosis in p53 mutant HPV negative head and neck squamous cell carcinoma

About 80% of patients with HPV negative head and neck squamous cell carcinoma are diagnosed at stage III or IV. In these cases, Surgical resection followed by (chemo-)radiotherapy is the standard treatment for most cases. However, many patients present with unresectable and/or resistant disease and even metastases, limiting therapeutic options. A common molecular defect in these tumours is the deactivation of the tumour suppressor gene TP53, frequently through inactivating mutations. Restoring TP53 function, combined with the standard chemoradiotherapy may enhance the therapeutic outcomes. In this study, the efficacy of two TP53 reactivating compound, APR-246 and COTI-2, was evaluated in combination with chemoradiotherapy on two different human HNSCC cell lines. Results highlight a synergistic effect of the combination treatment, significantly reducing clonogenic survival, spheroid growth and subcutaneous tumour growth in a preclinical murine model. Mechanistic investigation suggests that this effect is linked to redox imbalance caused by the generation of reactive oxygen species. This appears to play a key role in the Fenton reaction, further facilitated by an increase in DMT1 or decrease in FTH1 expression, leading to elevated cytosolic iron and lipid peroxide levels. Additionally, the reactive oxygen species may contribute towards the increase in both single and double strands breaks observed in several western blots. Overall, these results suggest that combining TP53 reactivation with chemoradiotherapy could trigger ferroptosis, improving tumour control in HNSCC.

cancer biology↗

bioRxiv2023

Ionizing radiation responses are incidental to desiccation responses in the bdelloid rotifer Adineta vaga

BackgroundThe remarkable resistance to ionizing radiation found in anhydrobiotic organisms, such as some bacteria, tardigrades, and bdelloid rotifers has been hypothesized to be incidental to the desiccation resistance. Both stresses produce reactive oxygen species and cause damage to DNA and other macromolecules. However, this hypothesis has only been investigated in a few species. ResultsIn this study, we analyzed the transcriptomic response of the bdelloid rotifer Adineta vaga to desiccation and to low- (X-rays) and high- (Fe) LET radiation to highlight the molecular and genetic mechanisms triggered by both stresses. We identified numerous genes encoding antioxidants, but also chaperones, that are constitutively highly expressed, which may contribute to the protection of proteins against oxidative stress during desiccation and ionizing radiation. We also detected a transcriptomic response common to desiccation and ionizing radiation with the over-expression of genes mainly involved in DNA repair and protein modifications but also genes with unknown functions being bdelloid-specific. A distinct transcriptomic response specific to rehydration was also found, with the over-expression of genes mainly encoding Late Embryogenesis Abundant proteins, specific Heat Shock Proteins, and glucose repressive proteins. ConclusionsThese results suggest that the extreme resistance of bdelloid rotifers to radiation might indeed be a consequence of their capacity to resist complete desiccation. This study paves the way to functional genetic experiments on A. vaga targeting promising candidate proteins playing central roles in radiation and desiccation resistance.

molecular biology↗

bioRxiv2022

Mouse Genomic Associations with Ex Vivo Sensitivity to Simulated Space Radiation

Exposure to ionizing radiation is considered by NASA to be a major health hazard for deep space exploration missions. Ionizing radiation sensitivity is modulated by both genomic and environmental factors. Understanding their contributions is crucial for designing experiments in model organisms, evaluating the risk of deep space (i.e. high-linear energy transfer, or LET, particle) radiation exposure in astronauts, and also selecting therapeutic irradiation regimes for cancer patients. We identified single nucleotide polymorphisms in 15 strains of mice, including 10 collaborative cross model strains and 5 founder strains, associated with spontaneous and ionizing radiation-induced ex vivo DNA damage quantified based on immunofluorescent 53BP1+ nuclear foci. Statistical analysis suggested an association with pathways primarily related to cellular signaling, metabolism, tumorigenesis and nervous system damage. We observed different genomic associations in early (4 and 8 hour) responses to different LET radiation, while later (24 hour) DNA damage responses showed a stronger overlap across all LETs. Furthermore, a subset of pathways was associated with spontaneous DNA damage, suggesting 53BP1+ foci as a potential biomarker for DNA integrity in mouse models. Based on our results, we suggest several mouse strains as new models to further study the impact of ionizing radiation and validate the identified genetic loci. We also highlight the importance of future human ex vivo studies to refine the association of genes and pathways with the DNA damage response to ionizing radiation and identify targets for space travel countermeasures.

genomics↗