Biology subjects

van de Ven, M.

Publications and source records attributed to van de Ven, M..

8 recordsLinked to original sources

bioRxiv2025

Efficiency of Anthelmintic Treatment and Its Effect on Microparasite Dynamics in Wild Mastomys natalensis

Co-infections between helminths and microparasites can influence disease dynamics with potential public health implications. However, establishing clear cause-and-effect relationships from natural populations remains challenging. One approach to address this is through perturbation experiments, where a specific parasite is selectively reduced to directly observe its impact on co-infecting parasites. While such experiments have been conducted in wild rodent populations, they have not yet been explored in Africa, despite the continents importance for emerging infectious diseases and zoonoses. In this study, we investigated potential helminth-microparasite interactions in wild Mastomys natalensis in Tanzania by using anthelmintics to reduce helminth infections. We first assessed the efficacy of two anthelmintic treatments, ivermectin and pyrantel pamoate, in wild-caught M. natalensis, finding that both treatments significantly reduced gastrointestinal nematodes, with pyrantel pamoate being more effective than ivermectin. Additionally, we examined how helminth reduction influenced microparasite prevalence. Our results show that pyrantel pamoate treatment was associated with a decrease in Morogoro virus seropositivity over time, while anthelmintic treatment had no significant effect on Bartonella infection probability.

ecology↗

bioRxiv2025

Mechanisms of dexamethasone-induced bone toxicity in developing bone: a single-cell perspective

AbstractGlucocorticoids, such as dexamethasone, are essential for treating severe childhood conditions, including cancer, organ transplantation, and inflammatory disorders. However, their long-term use can impair bone development, posing risks to pediatric bone health, which is vital for lifelong skeletal integrity. A mechanistic insight on how glucocorticoids negatively impact bone could improve decision-making in patient care to improve the quality of life for pediatric cancer patients and survivors. In this study, we aimed to elucidate the molecular mechanisms underlying dexamethasone-induced bone toxicity in developing bones using single-cell transcriptomics. We treated skeletally immature C57BL/6JRj mice with dexamethasone for 28 days, and assessed the bone architecture with micro-computed tomography, and characterized bone and bone marrow cells from the femurs using single-cell RNA sequencing. Our findings revealed a marked reduction in osteoblast and chondrocyte cell populations and impaired function of pre-osteoblasts. Additionally, dexamethasone adversely affected B cell subsets, significantly depleting early B cell progenitors while allowing some further developed immature B cells to persist. These cellular changes were accompanied by reduced longitudinal bone growth, compromised bone architecture, and increased bone fragility at the highest doses of dexamethasone. Interestingly, unlike observations in adults, dexamethasone did not enhance osteoclast activity in our model. Overall, our study suggests that the adverse effects of dexamethasone on bone development are primarily due to its impact on osteoblastic, chondroblastic and B cell lineages, disrupting the critical signaling crosstalk between the cells necessary for bone development and hematopoiesis. Layman summaryGlucocorticoids, like dexamethasone, are vital for treating severe childhood illnesses but can harm bone development when used long-term. This study investigated how dexamethasone affects bone health in young mice. Using advanced techniques, we found that dexamethasone reduced key bone-building cells (osteoblasts and chondrocytes) and weakened their function. It also disrupted immune cell development in the bone marrow, especially early B cells. These changes led to weaker, more fragile bones without increasing bone breakdown, unlike in adults. The findings highlight the need to carefully balance treatment benefits and risks for children to protect their bone health and overall well-being.

cancer biology↗

bioRxiv2022

Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors

BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR-defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPi) but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combined molecular profiling with functional analysis of the HR status of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent functional restoration of BRCA1/2. We observed restoration of HR in 64% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we found that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by the loss of PARG. Our combined multi-omics analysis catalogued additional genes and pathways potentially involved in modulating PARPi response.

cancer biology↗

bioRxiv2021

Combined SHP2 and ERK inhibition for the treatment of KRAS-driven Pancreatic Ductal Adenocarcinoma

Mutant KRAS is present in over 90% of pancreatic as well as 30-40% of lung and colorectal cancers and is one of the most common oncogenic drivers. Despite decades of research and the recent emergence of isoform-specific KRASG12C-inhibitors, most mutant KRAS isoforms, including the ones frequently associated with pancreatic ductal adenocarcinoma (PDAC), cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive mechanisms leading to tumor recurrence or resistance. We report here on the combined inhibition of SHP2, a non-receptor tyrosine phosphatase upstream of KRAS, and ERK, a serine/threonine kinase and a key molecule downstream of KRAS in PDAC. This combination shows synergistic anticancer activity in vitro, superior disruption of the MAPK pathway, and significantly increased apoptosis induction compared to single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination. Concurrent inhibition of SHP2 and ERK induces significant tumor regression in multiple PDAC mouse models. Finally, we show evidence that 18F-FDG PET scans can be used to detect and predict early drug responses in animal models. Based on these compelling results, we will investigate this drug combination in a clinical trial (SHERPA, SHP2 and ERK inhibition in pancreatic cancer, NCT04916236), enrolling patients with KRAS-mutant PDAC.

cancer biology↗

bioRxiv2021

Loss of p16INK4a in neuroblastoma cells induces shift to an immature state with mesenchymal characteristics and increases sensitivity to EGFR inhibitors

Homozygous inactivation of the CDKN2A locus is one of the most common genomic aberrations in human cancer. The locus codes for two unrelated and distinctly regulated proteins: p14ARF and p16INK4a, which inhibit MDM2 and CDK4/6, respectively. Loss of CDKN2A is also a recurrent event in relapsed neuroblastoma, a childhood tumour that arises from neural crest cells. To examine the consequences of the loss of the two distinct gene transcripts in neuroblastoma, we used the CRISPR-Cas9 system to knockout p14, p16 and p14+p16 in SY5Y cells. RNA sequencing of the transcriptome revealed a striking shift towards an immature Schwann cell precursor-like phenotype with mesenchymal characteristics, specifically in the p16 and p14+p16 knockouts. High-throughput drug screening of p16 and p14+p16 knockout clones identified a large increase in sensitivity to EGFR inhibitors. On protein level, we were able to confirm that EGFR pathway activation is higher in p14+p16 knockout cells and that treatment with the EGFR inhibitor afatinib resulted in higher levels of apoptosis. Afatinib also reduced tumour growth in vivo in xenografts transplanted with p14+p16 knockout SY5Y cells. Overall, our study suggests that CDKN2A deletion in neuroblastoma relates to a phenotypic shift towards a more progenitor like state and increases sensitivity to EGFR inhibitors.

cancer biology↗

bioRxiv2021

Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity

Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using this approach, we found that loss of CDK2 results in strong senescence induction in palbociclib-treated cells. Treatment with the CDK2 inhibitor indisulam, which phenocopies genetic CDK2 inactivation, led to sustained senescence induction when combined with palbociclib in various cell lines and lung cancer xenografts. Treating cells with indisulam led to downregulation of cyclin H, which prevented CDK2 activation. Combined treatment with palbociclib and indisulam induced a senescence program and sensitized cells to senolytic therapy. Our data indicate that inhibition of CDK2 through indisulam treatment can enhance senescence induction by CDK4/6 inhibition.

cancer biology↗

bioRxiv2019

Cancer modeling in colorectal organoids reveals intrinsic differences between oncogenic RAS and BRAF variants

Colorectal cancers (CRCs) with oncogenic mutations in RAS and BRAF are associated with anti-EGFR therapy resistance. Consequently, all RAS mutant CRC patients are being excluded from this therapy. However, heterogeneity in drug response has been reported between RAS mutant CRC patients. It is poorly understood to what extent such differences are derived from different genetic backgrounds or intrinsic differences between the various RAS pathway mutations. Therefore, using CRISPR technology we generated an isogenic panel of patient-derived CRC organoids with various RAS pathway mutations (i.e. KRASG12D, BRAFV600E, KRASG13D and NRASG12D). All RAS pathway mutants promote ERK activation and tumor growth. However, KRASG12D and BRAFV600E mutations in particular conferred robust resistance to anti-EGFR therapy, both in vitro and in vivo. Moreover, untreated KRASG13D mutants showed fastest growth in mice but remained sensitive to anti-EGFR therapy. Together, introducing mutation-specific oncogene signaling in CRC organoids resembles clinical phenotypes and improves understanding of genotype-phenotype correlations.

cancer biology↗

bioRxiv2018

Radiosensitivity is an acquired vulnerability of PARPi-resistant BRCA1-deficient tumors

The homologous recombination (HR) defect in BRCA1-associated cancers can be therapeutically exploited by the treatment with DNA-damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors. We and others previously reported that BRCA1-deficient tumors are initially hypersensitive to the inhibition of topoisomerase I/II and PARP, but acquire drug resistance through restoration of HR activity by the loss of end-resection antagonists of the 53BP1/RIF1/REV7/Shieldin/CST pathway. Here, we identified radiotherapy as an acquired vulnerability of 53BP1;BRCA1-deficient cells in vitro and in vivo. In contrast to the radioresistance caused by HR restoration through BRCA1 reconstitution, HR restoration by 53BP1 pathway inactivation further increases radiosensitivity. This highlights the relevance of this pathway for the repair of radiotherapy-induced damage. Moreover, our data show that BRCA1-mutated tumors that acquired drug resistance due to BRCA1-independent HR restoration can be targeted by radiotherapy.\n\nSTATEMENT OF SIGNIFICANCEIn this study, we uncovered radiosensitivity as a novel therapeutically exploitable vulnerability of BRCA1-deficient mouse mammary cells that have acquired drug resistance due to the loss of the 53BP1 pathway.

cancer biology↗