Biology subjects

van den Bos, H.

Publications and source records attributed to van den Bos, H..

4 recordsLinked to original sources

bioRxiv2024

CDK4 is co-amplified with either TP53 promoter gene fusions or MDM2 through distinct mechanisms in osteosarcoma

Amplification of the MDM2 and CDK4 genes on chromosome 12 is commonly associated with low-grade osteosarcomas. In this study, we conducted high-resolution genomic and transcriptomic analyses on 33 samples from 25 osteosarcomas, encompassing both high- and low-grade cases with MDM2 and/or CDK4 amplification. We identified four major subgroups: (i) low-grade osteosarcoma with chromosome 12 amplicons as the sole acquired alteration, (ii) high- and low-grade tumours with CDK4 and MDM2 amplification along with few changes affecting other chromosomes, (iii) high-grade osteosarcomas with heavily rearranged genomes including either CDK4 and MDM2 amplification or (iv) CDK4 amplification and TP53 structural alterations. The amplicons involving MDM2 exhibited signs of an initial chromothripsis event affecting chromosome 12. In contrast, there was no indication of a chromothripsis event on chromosome 12 in TP53-rearranged cases. Instead, the initial disruption of the TP53 locus resulted in breakage and repair processes that co-amplified the CDK4 locus. Furthermore, our investigation revealed recurring promoter swapping events that involved the regulatory regions of the FRS2, PLEKHA5, and TP53 genes. These events led to the ectopic expression of partner genes, with the ELF1 gene being upregulated by the FRS2 and TP53 promoter regions, respectively, in two distinct cases.

cancer biology↗

bioRxiv2022

Clinically-relevant treatment of PDX models reveals patterns of neuroblastoma chemoresistance

Chemotherapy resistance and relapses are common in high-risk neuroblastoma (NB), an aggressive pediatric solid tumor of the sympathetic nervous system. Here, we developed a clinically-relevant in vivo treatment protocol mimicking the first line five-chemotherapy treatment regimen of high-risk NB and applied this protocol to mice with MYCN-amplified NB patient-derived xenografts (PDXs). Genomic and transcriptomic analyses were used to reveal the genetic and non-genetic mechanisms involved in NB chemoresistance. We observed convergent and parallel evolution of key NB genetic aberrations over time. Intrinsic resistance to chemotherapy was associated with high genetic diversity and an embryonic phenotype. Relapsed NB PDX tumors with acquired resistance showed an immature mesenchymal-like phenotype resembling multipotent Schwann cell precursors that are found in the adrenal gland. NBs with a successful treatment response presented a lineage-committed adrenergic phenotype similar to normal neuroblasts, reduced cell cycle gene expression, and negative regulation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascade. NB organoids established from relapsed PDX tumors retained drug resistance, tumorigenicity, and transcriptional cell states ex vivo. This work sheds light on mechanisms involved in NB chemotherapy response in vivo and ex vivo using a clinically-relevant protocol, and emphasizes the importance of transcriptional cell states in treatment response. Detailed characterization of resistance mechanisms is essential for the development of novel treatment strategies in non-responsive or relapsed high-risk NB. One Sentence SummaryCOJEC chemotherapy treatment of neuroblastoma PDX models uncovers patterns of transcriptional plasticity and chemoresistance.

cancer biology↗

bioRxiv2020

PIDDosome-induced p53-activation for ploidy restriction facilitates hepatocarcinogenesis

Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. The PIDDosome multi-protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome-deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome-induced p53-activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome-deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro-tumorigenic effect of PIDDosome-mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome-deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts of survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and tumor cell density serves as a novel prognostic marker for recurrence free survival in HCC patients.

cancer biology↗

bioRxiv2019

Altering microtubule dynamics is synergistically toxic with inhibition of the spindle checkpoint

Chromosome instability (CIN) and aneuploidy are hallmarks of cancer. As the majority of cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings therefore suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics.

cancer biology↗