Biology subjects

Bakker, P.

Publications and source records attributed to Bakker, P..

4 recordsLinked to original sources

bioRxiv2024

Chromosomal instability promotes cell migration and invasion via EFEMP1 in extracellular vesicles

Triple-negative breast cancer (TNBC) is characterised by high rates of chromosomal instability (CIN) and a tumour microenvironment (TME) modulated by extracellular vesicles (EVs). To assess how CIN might affect the TME in TNBC, we studied the EV landscape of TNBC cell lines with induced CIN. We find that CIN leads to increased secretion of EVs and that these EVs promote cell migration of recipient cells. EVs are enriched for extracellular matrix (ECM) proteins, including EFEMP1. Indeed, modulation of EFEMP1 levels in EVs significantly alters migration behaviour of EV-treated cells. We show that EFEMP1 expression is regulated by STAT1, and that EVs from STAT1-deficient cells no longer promote migration, which can be rescued by overexpression of EFEMP1 in STAT1-null cells. Xenografting TNBC cells with EFEMP1 enriched cells promotes migration in zebrafish embryos, suggesting that EFEMP1 expression is a factor that promotes metastasis. Together our results uncover a novel role for CIN in shaping the TME of TNBC and identify EFEMP1 as a potential therapeutic target to prevent cell migration within the TME.

cancer biology↗

bioRxiv2023

CDC20 determines the sensitivity to spindle assembly checkpoint (SAC) inhibitors

Spindle assembly checkpoint (SAC) inhibitors are a recently developed class of drugs that perturb the regulation of chromosome segregation during division, induce chromosomal instability (CIN), and eventually lead to cell death. While they are currently in clinical trials for solid cancers, biomarkers to predict the response to SAC inhibitors are still lacking. We recently reported that aneuploid cancer cells are preferentially sensitive to SAC inhibition. Here, we investigated the molecular determinants of the response to SAC inhibition that underlies the differential sensitivity of aneuploid cells to these drugs. We found that this response was largely driven by the expression of CDC20, a main activator of the anaphase-promoting complex (APC/C), rather than by APC/C itself. Mechanistically, we discovered that CDC20 depletion prolonged metaphase duration, diminished mitotic errors, and reduced sensitivity to SAC inhibition. Aneuploid cells expressed high levels of CDC20 and experienced shorter metaphases and multiple mitotic errors, resulting in increased long-term sensitivity to SAC inhibition. Our findings propose high CDC20 expression as a favorable biomarker for SAC inhibition therapy and as an aneuploidy-induced therapeutic vulnerability.

cancer biology↗

bioRxiv2021

A single cell transcriptional roadmap for human pacemaker cell differentiation

Each heartbeat is triggered by the sinoatrial node, the natural pacemaker of the heart. Animal models have revealed that pacemaker cells share a common progenitor with the (pro)epicardium, and that the pacemaker cardiomyocytes further diversify into "transitional", "tail" and "head" subtypes. However, the underlying molecular mechanisms are poorly understood. Here, we studied the differentiation of human induced pluripotent stem cells into pacemaker cardiomyocytes. Single cell RNA sequencing identified the presence of myocardial populations resembling subtypes present in the formed sinoatrial node, and in addition revealed a side population of (pro)epicardial cells. Time-course trajectory analysis uncovered a role for WNT signaling in determining myocardial versus proepicardial cell fate. We experimentally demonstrate that presence of WNT signaling prior to the branching point of a common progenitor enhances proepicardial cell differentiation at the expense of myocardial pacemaker cells. Furthermore, we uncover a role for TGF{beta} and WNT signaling in differentiation towards transitional and head pacemaker subtypes, respectively. Our findings provide new biological insights into human pacemaker differentiation, open avenues for complex disease modeling and inform regenerative approaches.

developmental 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↗