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Transcription factors (TFs) are key components of the aberrant transcriptional programs in cancer cells. In this study, we used TF activity (TFa), inferred from the downstream regulons as a potential biomarker to identify associated genetic vulnerabilities in cancer cells. Our linear model framework, integrating TFa and genome-wide CRISPR knockout datasets identified 1,770 candidate TFa-target pairs across different cancer types and assessed their survival impact in patient data. As a proof of concept, through inhibitor screens and genetic depletion assays in cell lines, we validated the dependency of cell lines on predicted targets linked to TEAD1, the most prominent TF from our analysis. Overall, these candidate pairs represent an attractive resource for early-stage targets and drug discovery programs in oncology.

FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers1-5. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2-CD44-SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state., info:eu-repo/semantics/published

Merkel cell carcinoma (MCC) is a rare but very aggressive neuroendocrine cancer of the skin, with very limited therapeutic options. Although immunotherapy is effective in some cases, there is an unmet need for new therapeutic approaches in MCCs. In this issue of EMBO Molecular Medicine, Leiendecker et al identify a selective vulnerability of MCC for inhibitors of the lysine‐specific histone demethylase 1A (LSD1). LSD1 inhibitors promote differentiation of tumor cells toward normal Merkel cell fate, impairing tumor cell growth in vivo, and opening new avenues for the treatment of patients with MCC., F. Mauri and C. Blanpain discuss the identification of a selective vulnerability of Merkel cell carcinomas for LSD1, which could be used for establishing new therapeutic strategies, as reported by A. Obenauf and colleagues in this issue of EMBO Mol. Med.

Summary Background Asymmetric cell division (ACD) is a key process that allows different cell types to be generated at precisely defined times and positions. In Drosophila , neural precursor cells rely heavily on ACD to generate the different cell types in the nervous system. A conserved protein machinery that regulates ACD has been identified in Drosophila , but how this machinery acts to allow the establishment of differential cell fates is not entirely understood. Results To identify additional proteins required for ACD, we have carried out an in vivo live imaging RNAi screen for genes affecting the asymmetric segregation of Numb in Drosophila sensory organ precursor cells. We identify Banderuola (Bnd), an essential regulator of cell polarization, spindle orientation, and asymmetric protein localization in Drosophila neural precursor cells. Genetic and biochemical experiments show that Bnd acts together with the membrane-associated tumor suppressor Discs-large (Dlg) to establish antagonistic cortical domains during ACD. Inhibiting Bnd strongly enhances the dlg phenotype, causing massive brain tumors upon knockdown of both genes. Because the mammalian homologs of Bnd and Dlg are interacting as well, Bnd function might be conserved in vertebrates, and it might also regulate cell polarity in higher organisms. Conclusions Bnd is a novel regulator of ACD in different types of cells. Our data place Bnd at the top of the hierarchy of the factors involved in ACD, suggesting that its main function is to mediate the localization and function of the Dlg tumor suppressor. Bnd has an antioncogenic function that is redundant with Dlg, and the physical interaction between the two proteins is conserved in evolution.

The methodology of continuous improvement in manufacturing is a well-known practice originated by the ‘Japanese approach’ to industrial production. However, some needs still exist for an easy implementation of the improvement procedures it involves. In fact, in practical implementations in the manufacturing system, difficulties are encountered for clearly identifying the existing weak point to attack. To respond to this concern, the authors developed a special parameter called operating system effectiveness (OSE) that was very effective in measuring the performances of a manufacturing system and in detecting the causes of low productivity, thus offering a powerful tool for implementing process improvement measures. The article describes this approach by first setting the problem and reviewing the state of the art of similar methods already available in literature. Afterwards, the limits of existing methods are discussed and the new OSE parameter is presented and analysed in detail explaining how its compo...

Conjugation to SUMO is a reversible post-translational modification that regulates several transcription factors involved in cell proliferation, differentiation, and disease. The p53 tumor suppressor can be modified by SUMO-1 in mammalian cells, but the functional consequences of this modification are unclear. Here, we demonstrate that the Drosophila homolog of human p53 can be efficiently sumoylated in insect cells. We identify two lysine residues involved in SUMO attachment, one at the C terminus, between the DNA binding and oligomerization domains, and one at the N terminus of the protein. We find that sumoylation helps recruit Drosophila p53 to nuclear dot-like structures that can be marked by human PML and the Drosophila homologue of Daxx. We demonstrate that mutation of both sumoylation sites dramatically reduces the transcriptional activity of p53 and its ability to induce apoptosis in transgenic flies, providing in vivo evidence that sumoylation is critical for Drosophila p53 function., info:eu-repo/semantics/published

The nongenetic mechanisms required to sustain malignant tumor state are poorly understood. During the transition from benign tumors to malignant carcinoma, tumor cells need to repress differentiation and acquire invasive features. Using transcriptional profiling of cancer stem cells from benign tumors and malignant skin squamous cell carcinoma (SCC), we identified the nuclear receptor NR2F2 as uniquely expressed in malignant SCC. Using genetic gain of function and loss of function in vivo, we show that NR2F2 is essential for promoting the malignant tumor state by controlling tumor stemness and maintenance in mouse and human SCC. We demonstrate that NR2F2 promotes tumor cell proliferation, epithelial–mesenchymal transition and invasive features, while repressing tumor differentiation and immune cell infiltration by regulating a common transcriptional program in mouse and human SCCs. Altogether, we identify NR2F2 as a key regulator of malignant cancer stem cell functions that promotes tumor renewal and restricts differentiation to sustain a malignant tumor state. Blanpain and colleagues identify NR2F2 as a regulator of stemness and invasiveness that promotes tumor renewal and restricts differentiation to sustain squamous cell carcinomas.