Biology subjects

De Waele, J.

Publications and source records attributed to De Waele, J..

3 recordsLinked to original sources

bioRxiv2026

Focus on the edges: a biomolecular network of histone PTMs, metabolites and proteins unveils functional entanglement in AML

The cell phenotype is not a direct manifestation of the genotype but rather a product of cellular history and the environmental context. However, individual biomolecules cannot change independently and show coordinated behavior. To study this in acute myeloid leukemia (AML), we built a unique multi-omics biomolecular network made from proteins, metabolites and histone posttranslational modifications (hPTMs) sequentially extracted from each cell pellet. Edges between the nodes are measured directly using 400 LC-MSMS runs that cover 18 AML cell lines. We provide a novel conceptual framework to illustrate the different classes of functional entanglement between and within omics layers and present the data in three interactive data browsers to allow full community access. To help navigate the network, we approach it from the perspective of two biomolecular targets, i.e. CD34 and the epigenetic mark Histone H3 lysine 27 trimethylation (H3K27me3). Now, this easily accessible biomolecular network serves as a starting point for building and testing hypotheses and streamlining drug development, in the process positioning biomolecular associations center stage in understanding phenotypic complexity.

cancer biology↗

bioRxiv2025

HIF isoforms contribute distinctly during human NK cell activation

Hypoxia-inducible factors (HIFs) are critical transcriptional regulators that enable cellular adaptation to low oxygen environments. Natural killer (NK) cells are key effectors of innate immunity which frequently operate in hypoxic tissues during viral infection and tumor surveillance. In addition, HIF also play a role in NK cells beyond hypoxic adaptation. However, the distinct and overlapping roles of HIF-1 and HIF-2 in NK cell biology remain incompletely understood. In this study, we investigated the contribution of HIF-1 and HIF-2 to NK cell effector functioning in normoxia using pharmacological inhibition. When HIF-1 was inhibited, we observed a pronounced decline in cytotoxicity as well as IFN{gamma} and TNF production, but not granzyme B, accompanied by elevated mitochondrial reactive oxygen species. In contrast, HIF-2 did not alter these functions, nor did pan-HIF stabilization. These findings indicate a differential role of HIF-1 and HIF-2 in shaping NK cell responses in normoxia, at least during the acute activation phase as investigated here. Still, more mechanistic and contextual insights into the role of HIF isoforms in NK cells is warranted for future therapeutic applications.

immunology↗

bioRxiv2025

DRP1 depletion protects NK cells against hypoxia-induced dysfunction

Hypoxia within the tumor microenvironment poses a major barrier to the efficacy of NK cell-based immunotherapies for solid tumors. In this study, we investigated the influence of hypoxia on NK cell function and mitochondria. We found that hypoxia reduced NK cell cytotoxicity, mitochondrial content, and membrane potential, while increasing mtROS and inducing broad transcriptional changes in metabolic and stress response pathways. CAR engineering with CD70 and IL-15, while designed to enhance persistence and metabolic fitness, did not prevent hypoxia-induced impairment. Given the mitochondrial disruption, we then explored whether DRP1 ablation could mitigate hypoxia-induced dysfunction. Pharmacological inhibition of DRP1 restored mitochondrial content and cytotoxic function. To confirm the role of DRP1, we generated CRISPR-Cas9-mediated DRP1 KO NK cells, which preserved mitochondrial load and membrane potential under hypoxia. When armed with CD70-CAR-IL-15, DRP1KO cells retained cytotoxic activity under hypoxic conditions. These findings show that DRP1 inactivation can support NK cell function in hypoxic environments, and that metabolic engineering may enhance CAR NK cell efficacy in solid tumors. Graphical abstractNK cells become dysfunctional in hypoxic conditions, while DRP1KO NK cells retain their function. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/661011v2_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@2c3a96org.highwire.dtl.DTLVardef@1ba7d20org.highwire.dtl.DTLVardef@6ceeecorg.highwire.dtl.DTLVardef@1b9e0ca_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗