Plk1 Overexpression Impairs Chromosome Segregation and Suppresses Tumor Development

Polo-like kinase 1 (Plk1) is a serine-threonine protein kinase widely accepted as one of the master regulators of cell cycle. Overexpression of Plk1 is a frequent occurrence in an array of different human tumor types and it is usually correlated with poor prognosis in patients. However, very little is known about the exact role of Plk1 in tumorigenesis. Here, we use inducible mouse models to determine the in vivo consequences of Plk1 overexpression. During this study, we established that Plk1 is not an oncogene and overexpression of Plk1 has a strong tumor suppressive effect on Her2 or Kras driven breast cancer. Furthermore, tumors with elevated levels of Plk1 displayed evidence of whole genome doubling coupled with increased levels of aneuploidy. Histological characterization of murine mammary glands prior to tumor development affirmed a correlation between Plk1 overexpression and increase in genomic content at an early stage. Utilizing in vitro culture systems, we demonstrate that overexpression of Plk1 leads to reduced proliferation and causes polyploidy. Time-lapse imaging of mammary organoid cultures and mouse embryonic fibroblasts (MEFs) overexpressing Plk1 revealed that the polyploid cells originate due to impaired chromosome segregation as well as a failure of cytokinesis occurring during mitosis. Increased mitotic aberrations and supernumerary centrosomes accompanied these defective cell division processes. Mechanistically, the observed phenotype can be partially attributed to decrease of Shugoshin 1 (Sgo1) a target of Plk1, which is responsible for maintaining cohesion at the centromeres thus holding the sister chromatids together prior to anaphase. Premature loss of Sgo1 during prometaphase caused a partial or complete loss of cohesion. In this dissertation, we report that one of the major consequences of Plk1 overexpression is a staggering tumor suppressive effect, although this does not necessarily negate the possibility that Plk1 could promote tumor development under a different set of circumstances. Despite these findings, Plk1 inhibition in human tumors could still have a beneficial outcome because the kinase is indispensable for cell division. This work is not aimed at discouraging further research on Plk1 inhibitors; rather it provides a testament to the use of genetically engineered mouse models (GEMMs) that closely mimic human disease for pre-clinical testing. It is imperative to understand the molecular mechanisms and cellular processes leading up to tumor onset prior to the development of therapeutic strategies

Plk1 overexpression induces chromosomal instability and suppresses tumor development

Polo-like kinase 1 (Plk1) is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene and an attractive cancer target. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression results in abnormal chromosome segregation and cytokinesis, generating polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge, in a Plk1 kinase-dependent manner. In vivo, Plk1 overexpression prevents the development of Kras-induced and Her2-induced mammary gland tumors, in the presence of increased rates of chromosome instability. In patients, Plk1 overexpression correlates with improved survival in specific breast cancer subtypes. Therefore, despite the therapeutic benefits of inhibiting Plk1 due to its essential role in tumor cell cycles, Plk1 overexpression has tumor-suppressive properties by perturbing mitotic progression and cytokinesis.We are indebted to Stephen Taylor for the Sgo1 antibody. We thank Simone Kraut, Jessica Steiner, and the DKFZ light microscopy unit for excellent technical assistance. The results published here are in part based on data generated by TCGA pilot project (https://cancergenome.nih.gov/established by the NCI and the National Human Gen- ome Research Institute. The data were retrieved through dbGaP authorization (accession no. phs000178.v9.p8). S.V.V. was supported by the Marie Curie Network Ploidynet, funded by the European Union Seventh Framework Programme (FP7/2007–2013) under Grant Agreement #316964. L.S. is supported by a postdoctoral fellowship from Funda- cion Ramon Areces. Work in the R.S. laboratory was supported by an ERC starting grant (#281614), Marie Curie PCIG09-GA-2011 –293745 and the Howard Hughes Medical Institute. G.d.C. is funded by AECC Scientific Foundation (LABAE16017DECA). Work in the M.M. laboratory was supported by grants from the MINECO (SAF2015 –69920-R cofunded by ERDF-EU), Worldwide Cancer Research (WCR no. 150278), and Comunidad de Madrid (iLUNG-CM; B2017/BMD3884). The CNIO is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0510).S

Data associated with "Unveiling Tissue Microenvironment Dynamics: A Multimodal Imaging Pipeline to Decipher Cell-Specific Metabolic Functions"

SEM image with cells of interest (B cells – blue, T cells – red, Tumour cells – green) identified by confocal fluorescence analysis. Raw images from NanoSIMS showing isotope ratios for the B cell and T cell that are denoted in the SEM image. This data is associated with the manuscript - Unveiling Tissue Microenvironment Dynamics: A Multimodal Imaging Pipeline to Decipher Cell-Specific Metabolic Functions.</p

Bibliografi över arbeten som producerats av uppsalaslavister under året 1977

PLK1 is a mitotic regulator overexpressed in cancer; however, whether this overexpression causally contributes to tumor development is unclear. Here the authors produce an inducible mouse model to overexpress PLK1 and show that actually this can act as a tumor suppressor by perturbing mitotic progression and cytokinesis