Biology subjects

Stigter, E. C. A.

Publications and source records attributed to Stigter, E. C. A..

3 recordsLinked to original sources

bioRxiv2026

Hydrogen Peroxide induces resistance to DNA damage in a localization and p53 dependent manner.

Organisms need to be able to adapt to a changing environment in order to survive. The adaptive response invoked by a low dose of a stressor resulting in resistance to high levels of that stressor is known as hormesis and can even lead to lifespan extension of organisms. The exact mechanisms underlying stress-induced hormesis are unknown, although multiple studies pose mitochondria-derived Reactive Oxygen Species (ROS, e.g. H2O2) as an important contributor. Here we used chemo-genetic H2O2 production as a model to study ROS-dependent adaptive responses in a localization-dependent manner. We found that brief, sublethal H2O2 production at the nucleosomes provides p53-dependent resistance to a subsequent high dose of H2O2, whereas mitochondrial H2O2 production, surprisingly, does not. A multi-omics approach revealed that p53-induced hormesis is accompanied by metabolic rewiring that boosts reductive capacity, and that the increased stress resistance can mostly be attributed to its downstream target p21. Importantly, brief p53 stabilization also mounted protection against chemotherapy-induced DNA damage, suggesting that p53-dependent hormesis could be exploited to selectively protect healthy, p53-wildtype tissue from chemotherapy in the treatment of patients with p53 mutant tumors.

cancer biology↗

bioRxiv2022

Hsa-miR-31-5p controls a metabolic switch in psoriatic keratinocytes that identifies therapeutic intervention

Psoriasis is characterized by a combination of keratinocyte hyperproliferation and immune cell activation. Immune cell activation requires increased glucose consumption, consequently limiting glucose availability for other cell types like keratinocytes. In psoriasis Hsa-microRNA-31-5p (miR-31) is highly expressed in keratinocytes. Here we show that miR-31 expression in keratinocytes is induced by limited glucose availability and increases survival under limiting glucose conditions, by increasing glutamine metabolism. In addition, miR-31 induced glutamine metabolism results in secretion of specific metabolites (aspartate and glutamate) but also immuno-modulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibition of glutaminase (GLS) using CB-839 impedes miR31-induced metabolic rewiring and secretion of immuno-modulatory factors. Concordantly, pharmacological targeting of GLS alleviated psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.

immunology↗

bioRxiv2021

Rewiring glucose metabolism improves 5-FU efficacy in glycolytic p53-deficient colorectal tumors

5-fluorouracil (5-FU) is the backbone for chemotherapy in colorectal cancer (CRC). Response rates in patients are, however, limited to 50%. Despite the importance of 5-FU, the molecular mechanisms by which it induces toxicity remain unclear, limiting the development of strategies to improve efficacy. How fundamental aspects of cancer, such as driver mutations and phenotypic intra-tumor heterogeneity, relate to the 5-FU response is also ill-defined. This is largely due to the shortage of mechanistic studies executed in pre-clinical models that can faithfully recapitulate key CRC features. Here, we analyzed the 5-FU response in human organoids genetically engineered to reproduce the different stages of CRC progression. We find that 5-FU induces pyrimidine imbalance, which leads to DNA damage and cell death. Actively proliferating cancer (stem) cells are accordingly efficiently targeted by 5-FU. Importantly, p53 behaves as a discriminating factor for 5-FU sensitivity, whereas p53-deficiency leads to DNA damage-induced cell death, active p53 protects from these effects through inducing cell cycle arrest. Moreover, we find that targeting the Warburg effect, by rewiring glucose metabolism, enhances 5-FU toxicity by further altering the nucleotide pool and without increasing toxicity in healthy-non-transformed cells. Thus, targeting cancer metabolism in combination with replication stress-inducing chemotherapies emerges as a promising strategy for CRC treatment.

cancer biology↗