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Amsterdam-Zuidoost, Netherlands

Serresi M.,Netherlands Cancer Institute | Gargiulo G.,Netherlands Cancer Institute | Proost N.,Netherlands Cancer Institute | Siteur B.,Netherlands Cancer Institute | And 12 more authors.
Cancer Cell | Year: 2016

Polycomb repressive complexes (PRC) are frequently implicated in human cancer, acting either as oncogenes or tumor suppressors. Here, we show that PRC2 is a critical regulator of KRAS-driven non-small cell lung cancer progression. Modulation of PRC2 by either Ezh2 overexpression or Eed deletion enhances KRAS-driven adenomagenesis and inflammation, respectively. Eed-loss-driven inflammation leads to massive macrophage recruitment and marked decline in tissue function. Additional Trp53 inactivation activates a cell-autonomous epithelial-to-mesenchymal transition program leading to an invasive mucinous adenocarcinoma. A switch between methylated/acetylated chromatin underlies the tumor phenotypic evolution, prominently involving genes controlled by Hippo/Wnt signaling. Our observations in the mouse models were conserved in human cells. Importantly, PRC2 inactivation results in context-dependent phenotypic alterations, with implications for its therapeutic application. Serresi et al. identify PRC2 as a context-dependent tumor suppressor in KRAS-driven NSCLC. In p53 wild-type background, Eed loss promotes inflammation. Additional p53 inactivation leads to an invasive mucinous adenocarcinoma. A methylated/acetylated chromatin switch contributes to the phenotypic evolution. © 2016 Elsevier Inc.. Source

Blomen V.A.,Netherlands Cancer Institute | Majek P.,Austrian Academy of Sciences | Jae L.T.,Netherlands Cancer Institute | Bigenzahn J.W.,Austrian Academy of Sciences | And 17 more authors.
Science | Year: 2015

Although the genes essential for life have been identified in less complex model organisms, their elucidation in human cells has been hindered by technical barriers. We used extensive mutagenesis in haploid human cells to identify approximately 2000 genes required for optimal fitness under culture conditions. To study the principles of genetic interactions in human cells, we created a synthetic lethality network focused on the secretory pathway based exclusively on mutations. This revealed a genetic cross-talk governing Golgi homeostasis, an additional subunit of the human oligosaccharyltransferase complex, and a phosphatidylinositol 4-kinase β adaptor hijacked by viruses. The synthetic lethality map parallels observations made in yeast and projects a route forward to reveal genetic networks in diverse aspects of human cell biology. Source

Alexander S.,University of Houston | Weigelin B.,Radboud University Nijmegen | Winkler F.,German Cancer Research Center | Friedl P.,University of Houston | And 2 more authors.
Current Opinion in Cell Biology | Year: 2013

Key steps of cancer progression and therapy response depend upon interactions between cancer cells with the reactive tumour microenvironment. Intravital microscopy enables multi-modal and multi-scale monitoring of cancer progression as a dynamic step-wise process within anatomic and functional niches provided by the microenvironment. These niches deliver cell-derived and matrix-derived signals that enable cell subsets or single cancer cells to survive, migrate, grow, undergo dormancy, and escape immune surveillance. Beyond basic research, intravital microscopy has reached preclinical application to identify mechanisms of tumour-stroma interactions and outcome. We here summarise how n-dimensional 'dynamic histopathology' of tumours by intravital microscopy shapes mechanistic insight into cell-cell and cell-tissue interactions that underlie single-cell and collective cancer invasion, metastatic seeding at distant sites, immune evasion, and therapy responses. © 2013 Elsevier Ltd. Source

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