Biology subjects

Verdijk, R.

Publications and source records attributed to Verdijk, R..

3 recordsLinked to original sources

bioRxiv2025

Oropouche virus results in severe congenital disease in embryonic mice

The recent outbreak of Oropouche virus (OROV) in Latin-America with unprecedented reports of vertical transmission resulting in congenital malformations and fetal death, redefines the threat posed by this arbovirus. We here explore the teratogenic potential of an epidemic strain of the virus in a mouse model, whereby a low inoculum of OROV is injected into the placenta. The virus replicates efficiently in multiple embryonic organs, with high titers in the brain, and causes intrauterine growth restriction. Infected embryos display multi-organ pathology, including pneumonitis, myocarditis, steatohepatitis and severe neuropathology. Embryonic brains exhibit microcephaly, ventriculomegaly and extensive neural loss, mirroring findings in human fetal cases. A dramatic alteration of the neural cell population correlates with massive cell death, demonstrating the extreme cytotoxicity of OROV for the developing brain. The infection also triggers neuroinflammation characterized by cytokine upregulation, microglial activation and neutrophil infiltration. Altogether, our findings establish a link between congenital OROV infection and neurodevelopmental disease, highlighting its teratogenic potential.

microbiology↗

bioRxiv2025

Novel biomarkers in mutation-specific gene profiles highlight the involvement of COL9A3 in cancer cell plasticity in uveal melanoma

UM is a deadly ocular malignancy with well-described genetic alterations that predict disease outcome. However, our current understanding of the biological underpinnings of high-risk uveal melanoma progression remains relatively limited. On the basis of RNA expression profiles, we identified 12 novel biomarkers associated with high-risk UM, with protein expression validation of the 2 top markers RBFOX2 and COL9A3. Moreover, we investigated the functional contribution of COL9A3 via its overexpression in low-risk and high-risk UM cell lines. Our data suggest that COL9A3 enhances cell motility and cell proliferation and alters morphology specifically in high-risk UM cells. Furthermore, zebrafish xenograft studies revealed improved cell dissemination in a low-risk UM cell line upon overexpression of COL9A3, whereas a high-risk UM cell line remained under wild-type conditions. Interestingly, RNA sequencing revealed a high-stress profile in high-risk UM cell lines overexpressing COL9A3 and suggested the upregulation of plasticity markers, such as CD44, Nestin, EZH2, ABCB5, PAX3 and CD166, as a coping mechanism. These markers are known as differentiation markers during the development of melanocyte biogenesis and are implicated in plasticity in other high-risk cancers. The relationship between COL9A3 and plasticity was validated by multiplex immunohistochemistry of FFPE tissue, which demonstrated colocalization of COL9A3, CD44 and Nestin. BAP1mut-UM samples presented higher levels of COL9A3, CD44 and Nestin expression than EIF1AXmut- or SF3B1mut UM samples did. A positive correlation between COL9A3 and Nestin expression in triple-positive cells, regardless of the UM subtype, was observed. Together, our data suggest that COL9A3 is a novel high-risk biomarker that may be involved in UM cell plasticity and is most prevalent in BAP1mut UM.

cancer biology↗

bioRxiv2025

Transcriptional regulators FOXD1 and RBFOX2 contribute to metastatic capacity in BAP1mut uveal melanoma

Uveal melanoma is the most prevalent primary intraocular cancer, with a significant metastatic risk. This risk is dependent on the genetic drivers. Secondary mutations in EIF1AX, SF3B1 and BAP1 correlate with clinical outcomes and are recognized for their distinct transcriptomic and epigenetic profiles. Previously, we identified 480 genes involved in the development of ocular melanocytes. Top ranking genes RBFOX2 and FOXD1 were significantly associated with BAP1 UM and were independently correlated to poor progression. However, it is uncertain whether either RBFOX2 or FOXD1 have biological contribution to disease progression or are solely indicative. This study investigates if and how these high-risk associated transcription regulators FOXD1 and RBFOX2 could influence tumor progression through knock-out and overexpression models. Our results indicate that loss of RBFOX2 affects cell morphology, attachment and proliferation, particularly in BAP1neg cells. Additionally, both RBFOX2 and FOXD1 contribute to tumor growth and dissemination in zebrafish xenografts. Loss of either RBFOX2 or FOXD1 reduced tumor volume and cell dissemination, with the greatest effects seen in BAP1neg cells. Overexpression models demonstrated different morphological and invasive behavior depending on the genetic background, suggesting complex roles in a context dependent fashion. Overexpression of RBFOX2 did not alter BAP1pos cells yet made BAP1neg cells more aggressive in vitro and in vivo. This study underscores the influence of RBFOX2 and FOXD1 as important factors for UM progression.

cancer biology↗