Biology subjects

Foijer, F.

Publications and source records attributed to Foijer, F..

44 records · Page 3Linked to original sources

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↗

bioRxiv2020

Oncogenes hijack a constitutively active TP53 promoter in osteosarcoma

How massive genome rearrangements confer a competitive advantage to a cancer cell has remained an enigma. The malignant bone tumour osteosarcoma harbours an extreme number of structural variations and thereby holds the key to understand complex cancer genomes. Genome integrity in osteosarcoma is generally lost together with disruption of normal TP53 gene function, the latter commonly through either missense mutations or structural alterations that separate the promoter region from the coding parts of the gene. To unravel the consequences of a TP53 promoter relocated in this manner, we performed in-depth genetic analyses of osteosarcoma biopsies (n=148) and cell models. We show that TP53 structural variations are early events that not only facilitate further chromosomal alterations, but also allow the TP53 promoter to upregulate genes erroneously placed under its control. Paradoxically, many of the induced genes are part of the TP53-associated transcriptome, suggesting a need to counterbalance loss of TP53 function through separation-of-function mutations via promoter swapping. Our findings demonstrate how massive genome errors can functionally turn the promoter region of a tumour suppressor gene into a constitutively active oncogenic driver.

cancer biology↗

bioRxiv2019

Gene networks in cancer are biased by aneuploidies and sample impurities

Gene regulatory network inference is a standard technique for obtaining structured regulatory information from, among other data sources, gene expression measurements. Methods performing this task have been extensively evaluated on synthetic, and to a lesser extent real data sets. They are often applied to gene expression of human cancers. However, in contrast to the evaluations, these data sets often contain fewer samples, more potential regulatory links, and are biased by copy number aberrations as well as cell mixtures and sample impurities. Here, we take networks inferred from TCGA cohorts as an example to show that (1) transcription factor annotations are essential to obtaining reliable networks, and (2) even when taking these into account, we should expect between 20 and 80% of edges to be caused by copy number changes and cell mixtures rather than transcription factor regulation.

bioinformatics↗

bioRxiv2019

Replication Stress Generates Multiple Distinct Classes of Copy Number Alterations

BackgroundWe previously showed that a major driver of cancer chromosomal instability (CIN) is replication stress, the slowing or stalling of DNA replication. However, the precise drivers of replication stress in cancer and the mechanisms by which these cause CIN and influence tumour evolution remain unclear. Common fragile sites are well-known genomic locations of breakage after aphidicolin-induced replication stress, but their precise causes of fragility are debated, and additional genomic consequences of replication stress are not fully explored. ResultsUsing single cell sequencing we detected DNA copy number alterations (CNAs) caused by one cell cycle under replication stress in diploid non-transformed cells. Aphidicolin-induced replication stress caused multiple types of CNAs associated with different genomic regions and features. Coupling cell type-specific analysis of CNAs to gene expression and single cell replication timing analyses allowed us to pinpoint the causative large genes of the most recurrent chromosome-scale CNAs. In RPE1 cells these were largely confined to three sites on chromosomes 1, 2 and 7 and generated acentric lagging chromatin and micronuclei containing these chromosomes. Different replicative stresses generated distinct profiles of CNAs providing the potential to interpret specific replication stress mechanisms from cancer cells. ConclusionsChromosomal instability driven by replication stress occurs via focal CNAs and chromosome arm-scale changes, with the latter confined to a very small subset of chromosome regions, potentially heavily skewing cancer genome evolution trajectories. Single cell CNA analysis thus reveals new insights into the impact of replication stress on the genome and provides a platform to further dissect molecular mechanisms involved in the replication stress response and to gain insights into how replication stress fuels chromosomal instability in cancer.

molecular 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↗

bioRxiv2018

Single cell DNA sequencing reveals distinct molecular types of basal cell carcinoma with unique transcriptome features

Background: Aneuploidy, a hallmark of cancer, is the result of chromosomal instability (CIN) during mitosis. While some aneuploid cancers display stable karyotypes, other tumours display cell-to-cell karyotype variability indicative of CIN. CIN cancers are typically associated with poor clinical outcome, as they are endowed with the potential to adjust their genomes to changing conditions including therapy. To further explore this, we assessed the degree of aneuploidy and CIN in basal cell carcinoma (BCC) and investigated whether the karyotypic makeup of tumours was associated with distinct transcriptional responses. Patients and Methods: Samples from 11 BCC patients were processed for single-cell whole genome sequencing (scWGS) to measure aneuploidy and karyotype heterogeneity. In parallel, samples were processed for transcriptome analysis. Results: scWGS revealed different grades of aneuploidy between BCCs, ranging from euploidy to tumours with up to 7 aneusomic chromosomes. Importantly, a subset of BCCs displayed intratumour karyotype heterogeneity, indicating that CIN can play a role in BCC. Samples were clustered into three groups based on the level of aneuploidy and intratumour karyotype heterogeneity. Karyotype-driven group classification was also reflected by the tumour transcriptomes and revealed distinct gene expression signatures related to metabolism for aneuploid BCCs and a DNA damage signature for CIN BCCs. Conclusions: While BCCs are typically classified based on histopathological features, we find that BCCs can be stratified based on karyotypic landscape. Importantly, this classification is linked to distinct molecular features and could thus be the starting point of a molecular classification system for BCC including a readout for CIN. Importantly, the approach that we have developed is broadly applicable and could therefore also improve the diagnosis and treatment of other cancer types.

cancer biology↗

bioRxiv2018

Non-Random Mis-Segregation of Human Chromosomes.

Recurrent patterns of chromosomal changes (aneuploidy) are widespread in cancer. These patterns are mainly attributed to selection processes due to an assumption that human chromosomes carry equal chance of being mis-segregated into daughter cells when fidelity of cell division is compromised. Human chromosomes vary widely in size, gene density and other parameters that might generate bias in mis-segregation rates, however technological limitations have precluded a systematic and high throughput analysis of chromosome-specific aneuploidy. Here, using fluorescence In-Situ hybridization (FISH) imaging of specific centromeres coupled with high-throughput single cell analysis, as well as single-cell sequencing we show that human chromosome mis-segregation is non-random. Merotelic kinetochore attachment induced by nocodazole washout leads to elevated aneuploidy of a subset of chromosomes, and high rates of anaphase lagging of chromosomes 1 and 2. Mechanistically, we show that these chromosomes are prone to cohesion fatigue that results in anaphase lagging upon release from nocodazole or Eg5 inhibition. Our findings suggest that inherent properties of specific chromosomes can influence chromosome mis-segregation and aneuploidy, with implications for studies on aneuploidy in human disease.

cell biology↗

bioRxiv2018

Molecular basis of mitotic decline during human aging

Aneuploidy, an abnormal chromosome number, has been linked to aging and age-associated diseases, but the underlying molecular mechanisms remain unknown. Supported by direct live-cell imaging of young, middle-aged and old-aged primary human dermal fibroblasts, we found that aneuploidy increases with aging due to general dysfunction of the mitotic machinery. Increased chromosome segregation defects in elderly mitotic cells correlated with an early senescence-associated secretory phenotype (SASP) and repression of Forkhead box M1 (FoxM1), the transcription factor that drives expression of most G2/M genes. By restoring FoxM1 levels in elderly and Hutchison-Gilford Progeria Syndrome fibroblasts we prevented aneuploidy and, importantly, ameliorated cellular phenotypes associated with aging. Moreover, senescent fibroblasts isolated from elderly donors cultures were mostly aneuploid, suggesting that aneuploidy is a key player in the progression into full senescence phenotypes. Based on this feedback loop between cellular aging and aneuploidy, we propose modulation of mitotic efficiency through FoxM1 as a potential strategy against aging and progeria syndromes.

cell biology↗