Biology subjects

Van Aelst, L.

Publications and source records attributed to Van Aelst, L..

6 recordsLinked to original sources

bioRxiv2025

NOVEL SMALL-MOLECULE INHIBITORS OF THE PROTEIN KINASE DYRK: POTENTIAL THERAPEUTIC CANDIDATES IN CANCER

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) is crucial for normal brain development and its disruption has been linked to various cancers. DYRK1A drives glioblastoma (GBM) progression via stabilization of epidermal growth factor receptor (EGFR). Here we describe two, selective, benzothiazole-derived DYRK inhibitors, FC-2 and FC-3, obtained by structure-activity optimization of a natural product lead. Both compounds inhibit DYRK1A with nanomolar potency and display high selectivity across a kinase panel. The co-crystal structure of FC-3 with DYRK1A revealed ATP-competitive binding, with interactions at the hinge region and the DYRK-specific phenylalanine gatekeeper residue explaining target selectivity. Generation of inhibitor-resistant mutants confirmed DYRK1A as the primary cellular target. In GBM cell-models, FC-2 and FC-3 impaired neurosphere self-renewal, cell invasion, and EGFR stability, phenocopying DYRK1A loss. Both compounds crossed the blood-brain barrier and suppressed tumor growth, to prolong survival in intracranial xenografts. These findings identify FC-2 and FC-3 as selective small-molecule inhibitors of DYRK1A with potential therapeutic utility in GBM.

cancer biology↗

bioRxiv2025

Macropinocytosis enables metabolic recycling of extracellular DNA in cancer cells

Avid nutrient consumption is a metabolic hallmark of cancer and leads to regional depletion of key metabolites within the tumor microenvironment (TME). Cancer cells consequently employ diverse strategies to acquire the fuels needed for growth, including bulk uptake of the extracellular medium by macropinocytosis. Here, we show that breast and pancreatic cancer cells macropinocytically internalize extracellular DNA (exDNA), an abundant component of the TME, and deliver it to lysosomes for degradation. This provides a supply of nucleotides that sustains growth when de novo biosynthesis is impaired by glutamine restriction or pharmacological blockade. Mechanistically, this process is dependent on the non-redundant lysosomal equilibrative nucleoside transporter SLC29A3 (ENT3), which mediates the export of nucleosides from the lysosomal lumen into the cytosol. Accordingly, genetic ablation of SLC29A3 or pharmacological disruption of lysosomal function prevents exDNA scavenging and potently sensitizes breast tumors to antimetabolite chemotherapy in vivo. These findings reveal a previously unrecognized nutrient acquisition pathway through which cancer cells recycle exDNA into metabolic building blocks and highlight SLC29A3 as a mediator of metabolic flexibility and a potential target to improve chemotherapy response.

cancer biology↗

bioRxiv2025

PTP1B inhibition promotes microglial phagocytosis in Alzheimer's disease models by enhancing SYK signaling

Amyloid-{beta} (A{beta}) accumulation is a hallmark of Alzheimers disease (AD). Emerging evidence suggests that impaired microglial A{beta} phagocytosis is a key feature in AD, highlighting the therapeutic potential of enhancing this innate immune function. Here, we demonstrate that genetic deletion or pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) ameliorated memory deficits and reduced A{beta} burden in APP/PS1 mice. Moreover, we show that PTP1B was highly expressed in microglia, and its deficiency promoted a transcriptional shift toward immune activation and phagocytosis. Consistently, PTP1B deletion in microglia enhanced phagocytosis and metabolic fitness, supported by increased AKT-mTOR signaling, a pathway essential for meeting the energy demands of activation. Mechanistically, we identified spleen tyrosine kinase (SYK), a key regulator of microglial phagocytosis, as a direct substrate of PTP1B. Inhibition of SYK showed that PTP1B modulates microglial activation in a SYK-dependent manner. These findings established PTP1B as a critical modulator of microglial activation and a potential therapeutic target for AD.

molecular biology↗

bioRxiv2024

Restoring transient connectivity during development improves dysfunctions in fragile X mice

Early-generated circuits are critical for the maturation of cortical network activity and the formation of excitation/inhibition (E/I) balance. This process involves the maturation of specific populations of inhibitory neurons. While parvalbumin (PV)-expressing neurons have been associated with E/I impairments observed in neurodevelopmental disorders, somatostatin-expressing (SST) neurons have recently been shown to regulate PV neuron maturation by controlling neural dynamics in the developing cortex. SST neurons receive transient connections from the sensory thalamus, yet the implications of transient connectivity in neurodevelopmental disorders remain unknown. Here, we show that thalamocortical connectivity to SST neurons is persistent rather than transient in a mouse model of Fragile X syndrome. We were able to restore the transient dynamics using chemogenetics, which led to the recovery of fragile X-associated dysfunctions in circuit maturation and sensory-dependent behavior. Overall, our findings unveil the role of early transient dynamics in controlling downstream maturation of sensory functions.

neuroscience↗

bioRxiv2023

Antibody-directed extracellular proximity biotinylation reveals Contactin-1 regulates axo-axonic innervation of axon initial segments.

Axon initial segment (AIS) cell surface proteins mediate key biological processes in neurons including action potential initiation and axo-axonic synapse formation. However, few AIS cell surface proteins have been identified. Here, we used antibody-directed proximity biotinylation to define the cell surface proteins in close proximity to the AIS cell adhesion molecule Neurofascin. To determine the distributions of the identified proteins, we used CRISPR-mediated genome editing for insertion of epitope tags in the endogenous proteins. We found Contactin-1 (Cntn1) among the previously unknown AIS proteins we identified. Cntn1 is enriched at the AIS through interactions with Neurofascin and NrCAM. We further show that Cntn1 contributes to assembly of the AIS-extracellular matrix, and is required for AIS axo-axonic innervation by inhibitory basket cells in the cerebellum and inhibitory chandelier cells in the cortex.

neuroscience↗

bioRxiv2020

Oncogenic KRAS engages an RSK1/NF1 complex in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC. Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways and toxicity due to the targeting of normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil new potential therapeutic targets. Here, we used proximity labelling to identify protein interactors of active KRAS in PDAC cells. Fusions of wildtype (BirA-KRAS4B), mutant (BirA-KRAS4BG12D) and non-transforming and cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase were expressed in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 was enriched among proteins that selectively interacted with membrane-bound KRASG12D. RSK1 required the NF1 and SPRED proteins to interact with KRAS-GTP at the membrane. In both murine and human PDAC lines, membrane-targeted RSK1 was tolerated but inhibited cell proliferation following oncogenic KRAS abrogation to reveal a negative feedback role for membrane-localized RSK1 on wild-type KRAS. Inhibition of the wild-type KRAS, which has been previously proposed to suppress KRAS oncogenesis, may partially explain how RSK1 has been identified as a dependency in some KRAS mutant cells and may provide an additional function for NF1 in tumorigenesis. Significance StatementFor decades, KRAS interactors have been sought after as potential therapeutic targets in KRAS mutant cancers, especially pancreatic adenocarcinoma (PDAC). Our proximity labeling screen with KRAS in PDAC cells highlight RSK1 as a notable mutant-specific interactor. Functionally, we show that RSK1 mediates negative feedback on wild-type KRAS in PDAC cells.

cancer biology↗