Bourbonnais, J. | Search bioRxiv

bioRxiv2023

53BP1 mediates sensitivity to chemotherapy and is associated with poor clinical outcomes in high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecological malignancy in North American women. At a cellular level, the current first-line chemotherapies cause DNA-damage and activate the DNA damage response signalling cascade. Here we explore the role of 53BP1, a central mediator of the DNA damage response, in HGSOC chemotherapy outcomes. Tissue 53BP1 protein levels were quantified in two independent HGSOC cohorts, the COEUR validation cohort (n = 173) and CHUM cohort (n = 56). Univariate and multivariate analyses showed that high nuclear 53BP1 levels in ovarian cancer cells were strongly associated with poor disease-specific survival in both cohorts. High 53BP1 was associated with poor progression-free survival (PFS) in the COEUR cohort, and trended towards poor PFS in the CHUM cohort. These findings were validated by whole-tumour TP53BP1 mRNA of the TCGA Firehose Legacy cohort (n = 591) in which high TP53BP1 mRNA levels were associated with poor overall survival on multivariate analysis. In HGSOC cell lines, 53BP1 levels were positively correlated with resistance to carboplatin using colony formation assay, and depletion of 53BP1 sensitized resistant cell lines to genotoxic therapies. These results suggest that 53BP1 is associated with poor prognosis in HGSOC and may mediate this relationship by modulating cellular sensitivity to chemotherapy. Statement of translational relevanceCurrent first-line chemotherapies in ovarian cancer cause DNA damage and activate the DNA damage response, culminating in the taking of cell fate decisions. 53BP1 is a central mediator in this signalling cascade, where it is involved at multiple levels: signal amplification, recruitment of effectors, DNA repair pathway choice, and cell cycle regulation. However, its role in ovarian cancer treatment outcomes remains unknown. In this study, we found that 53BP1 correlated with poor clinical outcomes in three ovarian cancer patient cohorts and mediated carboplatin sensitivity in ovarian cancer cells. These results reveal 53BP1 and the DNA damage response as important actors in ovarian cancer treatment response. Though further studies are necessary to gain a more complete understanding of their involvement in clinical outcomes, they appear as promising candidates for potential therapeutic targeting in ovarian cancer.

cancer biology↗

bioRxiv2023

KCC2 as a novel biomarker and therapeutic target for motoneuron degenerative disease

Hyperexcitability in cells throughout the corticospinal tract is a presymptomatic feature of amyotrophic lateral sclerosis (ALS) associated with lethal motor degeneration 1-6. Disinhibition is a possible cause of this hyperexcitability, potentially implicating the central nervous system-specific potassium-chloride cotransporter, KCC2, a core regulator of the strength of GABAergic neurotransmission linked to several neurological disorders 7-11. Here, we show that KCC2 is downregulated in the membrane of motor cortex neurons from post-mortem SOD1-, C9orf72- and sporadic ALS is patients. Increased protein levels of KCC2 were found in plasma and cerebral spinal fluid of ALS patients and mice harbouring the SOD1*G93A mutation. Longitudinal analysis of disease progression in both SOD1*G93A and Prp-TDP43*A315T mice revealed a decrease of KCC2 membrane levels in cortical and spinal motor neurons which were already present at the presymptomatic phase. Using KCC2-enhancing compounds, CLP290 and prochlorperazine (PCPZ) restored KCC2 membrane expression and function, delayed motor deficit onset, and extended lifespan up to two months in mutant mice. Human-derived neurons differentiated from iPSC harbouring the SOD1*G93A mutation displayed KCC2 deficits which PCPZ treatment rescued. Acute administration of KCC2 enhancers restored chloride transport in presymptomatic and symptomatic mice and reversed motor neuron hyperexcitability in awake behaving mutant mice. These findings identify KCC2 as both an early biomarker and a disease-modifying therapeutic target for ALS.

neuroscience↗