Selected Articles from This Issue

Hepatoblastoma (HBL) and fibrolamellar carcinoma (FLC) are both rare forms of liver cancer with largely unstudied mechanisms of pathogenesis. In their study, Fleifil and colleagues explored the role of J-PKAc–β-catenin and the cohesin ring in oncogenic activation. Immunoprecipitation assays revealed that a complex of CTCF, Rad21, SMC3 and SMC1 forms in HBL, and that these proteins bind to CEGRs/ALCD, the CTCF consensus binding site, and to the NRF2 promoter through TCF4/TCF4–β-catenin interaction. Immunofluorescence and BET bromodomain inhibition studies using liver cancer cell lines showed that the cohesin ring cooperates with ph-S675–β-catenin in activating CEGRs/ALCD-containing oncogenes and promoting cell proliferation in a Rad21-dependent manner. The authors also found that FLC patients had increased levels of cohesin ring proteins and β-catenin–CEGRs/ALCD targets. Further ChIP analysis demonstrated that the cohesin ring binds to the Thy1 promoter and CEGR/ALCD in FLC. Overall, this study illustrates the cooperation of J-PKAc–β-catenin and the cohesin ring in HBL and FLC and emphasizes the importance of understanding the complex mechanisms underlying oncogenesis.Merkel cell carcinoma (MCC) is a rare skin cancer often caused by Merkel cell polyomavirus (MCPyV). Despite this, our understanding of MCPyV genomic integration and its functional implications is limited. To address this deficiency, Smith and colleagues evaluated the tumor mutational burden and copy-number variation present in virus-positive (VP) and virus-negative (VN) MCC and created an informatics pipeline for MCPyV genomic integration analysis. Genomic analyses of VP-MCC and VN-MCC identified a higher number of activating alterations in VN-MCC, specifically in proto-oncogenes and genes driving epigenetic silencing, including KMT2B, KMT2C, KMT2D, DNMT1, and ARID1B. Inactivating mutations for key tumor suppressor genes, such as RB1, TP53, NOTCH1, and PTEN were also found in the majority of VN-MCC tumors. Genomic scores based on tumor mutational burden and copy-number variation in patients with lymph node metastasis and MCPyV showed patients with high TMB and CNV had poorer survival compared to patients with low TMB and CNV. Taken together, this study dissects MCPyV genomic integration and introduces MCPyViewer, a resource-based informatics pipeline that can be used to visualize MCPyV integration sites.HNF4α is an important transcriptional regulator for the classical subtype of pancreatic ductal adenocarcinoma (PDAC). To determine the significance of HNF4α isoforms in PDAC subtypes, Fang and colleagues studied how isoforms driven by either the P1 or P2 promoter contribute to PDAC progression and differentiation. In vitro analysis of the P1 isoform, HNF4α2, and the P2 isoform, HNF4α8, revealed that expression of P1 and P2 isoforms hinder PDAC proliferation. RNA sequencing and GSEA of PDAC cells expressing either isoform further showed that the P1 isoform strongly inhibits signatures for normal squamous cell and basal-like PDAC. A scatterplot of the DEGs significantly regulated by both isoforms and ChIP sequencing further demonstrated that P1 isoforms are stronger transcriptional regulators compared to P2 isoforms. CRISPRi competition assays using P1 and P2 knockdown PDAC cells also found a greater functional effect for dual knockdown cells, indicating their partial redundancy. Cell line dependent P1 and P2 transcriptional regulation was also observed. These findings altogether highlight the role of HNF4α isoforms across PDAC subtypes and suggest that isoforms of key transcriptional regulators may play important roles in cancer progression.