Biology subjects

van Ijcken, W. F. J.

Publications and source records attributed to van Ijcken, W. F. J..

4 recordsLinked to original sources

bioRxiv2025

Metabolic Alterations driven by PFKFB3 upregulation confer Resistance to Trastuzumab in HER2-Positive Breast Cancer.

AimsResistance to anti-HER2 therapies, particularly trastuzumab, remains a major obstacle in the treatment of HER2-positive (HER2+) breast cancer. This study aims to uncover novel mechanisms driving trastuzumab resistance with a focus on the immune component, key mediator of trastuzumab efficacy. MethodsWe developed an isogenic cell line-derived xenograft model to perform transcriptome-wide analyses of trastuzumab-sensitive and -resistant tumors. To validate key findings, we employed a 3D cancer-immune co-culture system capable of quantifying antibody-dependent cellular cytotoxicity (ADCC). ResultsTranscriptomic profiling revealed how trastuzumab treatment shifts tumor transcriptomes, including changes that remodel the metabolic landscape and distinct gene signatures associated with resistance, notably the upregulation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Functional studies demonstrated that PFKFB3 promotes trastuzumab resistance by inducing metabolic rewiring and reducing ADCC. Silencing PFKFB3 restored immune-mediated cytotoxicity. Clinical dataset analyses confirmed that elevated PFKFB3 expression correlates with reduced overall and progression-free survival, and with incomplete pathological response to trastuzumab. ConclusionsPFKFB3 upregulation drives metabolic adaptations that confer resistance to trastuzumab in HER2+ breast cancer. These findings highlight PFKFB3 as a promising therapeutic target to overcome resistance and improve patient outcomes. HighlightsO_LIPFKFB3 upregulation promotes trastuzumab resistance in HER2+ breast cancer. C_LIO_LITranscriptomic profiling reveals metabolic shifts linked to resistance. C_LIO_LISilencing PFKFB3 restores ADCC and sensitizes cancer cells to trastuzumab. C_LIO_LIHigh PFKFB3 expression correlates with poor survival and treatment response. C_LIO_LIPFKFB3 is a potential therapeutic target to overcome trastuzumab resistance. C_LI

cancer biology↗

bioRxiv2024

Purkinje cell intrinsic activity shapes cerebellar development and function

The emergence of functional cerebellar circuits is heavily influenced by activity-dependent processes. However, the role of intrinsic activity in Purkinje neurons, independent of external input, in driving cerebellar development remains less understood. Here, we demonstrate that before synaptic networks mature, Purkinje cell intrinsic activity is essential for regulating dendrite growth, establishing connections with cerebellar nuclei, and ensuring proper cerebellar function. Disrupting this activity during the postnatal period impairs motor function, with earlier disruptions causing more severe effects. Importantly, only disruptions during early development lead to pronounced defects in cellular morphology, highlighting key temporal windows for dendritic growth and maturation. Transcriptomic analysis revealed that early intrinsic activity drives the expression of activity-dependent genes, such as Prkcg and Car8, which are essential for dendritic growth. Our findings emphasize the importance of temporally-specific intrinsic activity in Purkinje cells for guiding cerebellar circuit development, providing a potential common mechanism underlying cerebellum-related disorders.

neuroscience↗

bioRxiv2022

CLASP1 is essential for neonatal lung function and survival in mice

The first breath of air at birth marks the beginning of extrauterine life, and breathing problems due to incomplete lung development or acute respiratory distress are common in premature babies and respiratory diseases. However, the underlying molecular mechanisms remain poorly understood. Here we show that the microtubule plus-end-tracking protein CLASP1 is required for neonatal lung function and survival. CLASP1 is expressed in the lungs and associated respiratory structures throughout embryonic development. Clasp1 disruption in mice caused intrauterine growth restriction and neonatal lethality due to acute respiratory failure. Knockout animals showed impaired lung inflation associated with smaller rib cage formation and abnormal diaphragm innervation. Live-cell analysis of microtubule dynamics in cultured hippocampal neurons revealed an increased catastrophe rate, consistent with a role of CLASP1 in neurite outgrowth. Histological and gene expression studies indicated that CLASP1 is required for normal pneumocyte differentiation and fetal lung maturation. Thus, CLASP1-mediated regulation of microtubule dynamics assists multiple systems essential for neonatal lung function and survival.

developmental biology↗

bioRxiv2017

Lewy pathology in Parkinson’s disease consists of a crowded organellar membranous medley

Parkinsons disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites, which are neuronal inclusions that are immunopositive for the protein -synuclein. In-depth ultrastructural analysis of this Lewy pathology is crucial to understanding pathogenesis and progression of the disease. Using correlative light and electron microscopy/tomography on brain tissue from five Parkinsons disease brain donors, we identified -synuclein immunopositive Lewy pathology and could show that the majority of these features including Lewy bodies and Lewy neurites primarily consists of a crowded membranous medley of vesicular structures and dysmorphic organelles. Only a small fraction of observed Lewy bodies contained predominant proteinaceous filaments, as previously described. The crowding of organellar components was confirmed by STED- based super-resolution microscopy, and high lipid content within the -synuclein immunopositive inclusions was corroborated by confocal imaging, CARS/FTIR imaging and lipidomics. Applying this correlative high-resolution imaging and biophysical approach, we discovered in the postmortem brain of Parkinsons patients a subcellular protein-lipid compartmentalization not previously described in Lewy pathology.

neuroscience↗