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Twist1 promotes epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and cancer stem cell (CSC) properties. However, it remains unclear whether Twist1 is also required for tumor initiation and whether Twist1-induced cancer stemness and EMT are functionally linked. Using a conditional deletion of Twist1 at different stages of skin carcinogenesis, we show that Twist1 is required for skin tumor initiation and progression in a gene-dosage-dependent manner. Moreover, conditional ablation of Twist1 in benign tumors leads to increased apoptosis, reduced cell proliferation, and defective tumor maintenance and propagation independently of its EMT-inducing abilities. Concomitant deletion of Twist1 and p53 rescues the apoptotic response, but not the cell proliferation and propagation defects. These results reveal that Twist1 is required for tumor initiation and maintenance in a p53-dependent and -independent manner. Importantly, our findings also indicate that tumor stemness and EMT can be regulated by distinct mechanisms.

Very little to no improvement in overall survival has been seen in patients with advanced non-resectable cutaneous melanoma or metastatic uveal melanoma in decades, highlighting the need for novel therapeutic options. In this study we investigated as a potential novel therapeutic intervention for both cutaneous and uveal melanoma patients a combination of the broad spectrum HDAC inhibitor quisinostat and pan-CDK inhibitor flavopiridol. Both drugs are currently in clinical trials reducing time from bench to bedside. Combining quisinostat and flavopiridol shows a synergistic reduction in cell viability of all melanoma cell lines tested, irrespective of their driver mutations. This synergism was also observed in BRAFV600E mutant melanoma that had acquired resistance to BRAF inhibition. Mechanistically, loss of cell viability was, at least partly, due to induction of apoptotic cell death. The combination was also effectively inducing tumor regression in a preclinical setting, namely a patient-derived tumor xenograft (PDX) model of cutaneous melanoma, without increasing adverse effects. We propose that the quisinostat/flavopiridol combination is a promising therapeutic option for both cutaneous and uveal metastatic melanoma patients, independent of their mutational status or (acquired) resistance to BRAF inhibition.

Molecular classification of endometrial cancer identified distinct molecular subgroups. However, the largest subset of endometrial cancers remains poorly characterized and is referred to as the "nonspecific molecular profile" (NSMP) subgroup. Here, we aimed at refining the classification of this subgroup by profiling somatic copy-number aberrations (SCNAs). SCNAs were analyzed in 141 endometrial cancers using whole-genome SNP arrays and pooled with 361 endometrial cancers from The Cancer Genome Atlas. Genomic Identification of Significant Targets in Cancer (GISTIC) identified statistically enriched SCNAs and penalized Cox regression assessed survival effects. The prognostic significance of relevant SCNAs was validated using multiplex ligation-dependent probe amplification in 840 endometrial cancers from the PORTEC-1/2 trials. Copy-number status of genes was correlated with gene expression to identify potential cancer drivers. One plausible oncogene was validated using antisense oligonucleotide-based strategy. SCNAs affecting chromosome 1q32.1 significantly correlated with worse relapse-free survival (RFS) in the NSMP subgroup (HR, 2.12; 95% CI, 1.26-3.59; = 0.005). This effect was replicated in NSMP endometrial cancers from PORTEC-1/2 (HR, 2.34; 95% CI, 1.17-4.70; = 0.017). A new molecular classification including the 1q32.1 amplification improved risk prediction of recurrence. gene expression strongly correlated with 1q32.1 amplification. Silencing inhibited cell growth in cell lines carrying 1q32.1 amplification, but not in those without amplification., increasing expression in nonamplified cell lines stimulated cell proliferation. 1q32.1 amplification was identified as a prognostic marker for poorly characterized NSMP endometrial cancers, refining the molecular classification of this subgroup. We functionally validated as a potential oncogenic driver in the 1q32.1 region..

Autosomal recessive IRF7 deficiency was previously reported in three patients with single critical influenza or COVID-19 pneumonia episodes. The patients’ fibroblasts and plasmacytoid dendritic cells produced no detectable type I and III IFNs, except IFN-β. Having discovered four new patients, we describe the genetic, immunological, and clinical features of seven IRF7-deficient patients from six families and five ancestries. Five were homozygous and two were compound heterozygous for IRF7 variants. Patients typically had one episode of pulmonary viral disease. Age at onset was surprisingly broad, from 6 mo to 50 yr (mean age 29 yr). The respiratory viruses implicated included SARS-CoV-2, influenza virus, respiratory syncytial virus, and adenovirus. Serological analyses indicated previous infections with many common viruses. Cellular analyses revealed strong antiviral immunity and expanded populations of influenza- and SARS-CoV-2–specific memory CD4+ and CD8+ T cells. IRF7-deficient individuals are prone to viral infections of the respiratory tract but are otherwise healthy, potentially due to residual IFN-β and compensatory adaptive immunity.

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Transcriptional upregulation of a variety of signaling genes is a key feature of PLAG1-induced tumorigenesis. The PLAG1 gene is mainly expressed during embryogenesis and mobilization of its oncogenic potential in human tumors results from genetic aberrations. The oncogenic capacity of the PLAG1 gene was initially demonstrated by various standard experimental approaches in vitro. The oncogenic potential of the PLAG1 gene was further demonstrated by the generation of a versatile tumor mouse model system with Cre-mediated expression activation of the PLAG1 gene. In previous studies, it was demonstrated that the PLAG1-encoded protein is a genuine transcription factor, which recognizes a specific bipartite DNA sequence motif and activates a variety of target genes among which genes of the Igf and Wnt signaling pathways. In an attempt to interfere with the oncogenic PLAG1 transcription factor, the possible effect of a variety of natural products including various polyphenols was studied. Initially, PLAG1 transduced Balb/c-3T3 expressing high levels of PLAG1 were screened for the possible effect of a variety of polyphenols on the PLAG1-induced upregulation of various established PLAG1 target genes such as for instance Igf2. The polyphenolic compound curcumin was selected for further studies since, in the initial experiments, it was shown to exhibit downregulation of Igf2 expression as well as that of other well-established PLAG1 target genes such as H19, Dlk1, and Gtl2. Evaluation of the expression of various genes which lack the PLAG1-specific bipartite DNA binding motif in their promoter regions revealed no effect of curcumin; e.g. Plag1, Wnt6 and Ctnnb1. The observation that preferentially the expression of PLAG1 target genes was affected by curcumin raised the possibility that curcumin might interfere with the binding of the PLAG1 transcription factor to its specific DNA binding sites in the promoter regions of the tested PLAG1 target genes. To test this hypothesis, the effect of curcumin on the expression of two reporter gene constructs was studied. These reporter constructs consisted of the luciferase gene under expression control of a HSK-tk promoter with either three wild-type PLAG1-specific DNA binding motifs or, as a control, three mutated forms of it upstream of HSV-tk. The results of these experiments suggested that curcumin indeed might interfere directly with the binding of the PLAG1 transcription factor protein to its cognate DNA binding motif. To further substantiate these results in an independent way, EMSA experiments are being performed. Altogether, the results of these studies seem to favor the notion that curcumin could directly affect the PLAG1-induced tumorigenic process in vivo by interfering with the binding of the PLAG1 transcription factor to its cognate binding sites in promoter regions of target genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1981. doi:1538-7445.AM2012-1981