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Cancer genomics has enabled the exhaustive molecular characterization of tumors and exposed hepatocellular carcinoma (HCC) as among the most complex cancers. This complexity is paralleled by dozens of mouse models that generate histologically similar tumors but have not been systematically validated at the molecular level. Accurate models of the molecular pathogenesis of HCC are essential for biomedical progress; therefore we compared genomic and transcriptomic profiles of four separate mouse models [MUP transgenic, TAK1-knockout, carcinogen-driven diethylnitrosamine (DEN), and Stelic Animal Model (STAM)] with those of 987 HCC patients with distinct etiologies. These four models differed substantially in their mutational load, mutational signatures, affected genes and pathways, and transcriptomes. STAM tumors were most molecularly similar to human HCC, with frequent mutations in Ctnnb1, similar pathway alterations, and high transcriptomic similarity to high-grade, proliferative human tumors with poor prognosis. In contrast, TAK1 tumors better reflected the mutational signature of human HCC and were transcriptionally similar to low-grade human tumors. DEN tumors were least similar to human disease and almost universally carried the Braf V637E mutation, which is rarely found in human HCC. Immune analysis revealed that strain-specific MHC-I genotype can influence the molecular makeup of murine tumors. Thus, different mouse models of HCC recapitulate distinct aspects of HCC biology, and their use should be adapted to specific questions based on the molecular features provided here.

Metastatic spread is the leading cause of cancer mortality. Breast cancer (BCa) metastatic recurrence can happen years after removal of the primary tumor. Here we show that Ubc13, an E2 enzyme that catalyzes K63-linked protein polyubiquitination, is largely dispensable for primary mammary tumor growth but is required for metastatic spread and lung colonization by BCa cells. Loss of Ubc13 inhibited BCa growth and survival only at metastatic sites. Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFβ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa. Significance We demonstrate that ubiquitin-conjugating enzyme Ubc13, whose expression is elevated in primary and metastatic breast cancer (BCa), promotes metastatic spread of BCa cells by controlling their lung-colonizing ability while having little effect on primary tumor growth. Mechanistically, Ubc13 is required for TGFβ-induced non-SMAD signaling via TAK1 and p38, a pathway that is first activated in the primary tumor. An Ubc13- and p38-dependent metastatic gene signature was identified, explaining how p38 may control metastasis and providing a measure for monitoring the effectiveness of pharmacologic p38 inhibition, which inhibits the growth of established metastatic lesions. We suggest that p38 inhibition should be considered as a potential treatment for metastatic BCa.

E-cadherin is an important adhesion molecule whose loss is associated with progression and poor prognosis of liver cancer. However, it is unclear whether the loss of E-cadherin is a real culprit or a bystander in liver cancer progression. In addition, the precise role of E-cadherin in maintaining liver homeostasis is also still unknown, especially in vivo. Here we demonstrate that liver-specific E-cadherin knockout mice develop spontaneous periportal inflammation via an impaired intrahepatic biliary network, as well as periductal fibrosis, which resembles primary sclerosing cholangitis. Inducible gene knockout studies identified E-cadherin loss in biliary epithelial cells as a causal factor of cholangitis induction. Furthermore, a few of the E-cadherin knockout mice developed spontaneous liver cancer. When knockout of E-cadherin is combined with Ras activation or chemical carcinogen administration, E-cadherin knockout mice display markedly accelerated carcinogenesis and an invasive phenotype associated with epithelial–mesenchymal transition, up-regulation of stem cell markers, and elevated ERK activation. Also in human hepatocellular carcinoma, E-cadherin loss correlates with increased expression of mesenchymal and stem cell markers, and silencing of E-cadherin in hepatocellular carcinoma cell lines causes epithelial–mesenchymal transition and increased invasiveness, suggesting that E-cadherin loss can be a causal factor of these phenotypes. Thus, E-cadherin plays critical roles in maintaining homeostasis and suppressing carcinogenesis in the liver.

Newborn screening for immunodeficiency has led to the identification of numerous cases for which the causal etiology is unknown. Here we report the diagnosis of T lymphopenia of unknown etiology in a male proband. Whole exome sequencing (WES) was employed to nominate candidate variants, which were then analyzed functionally in zebrafish and in mice bearing orthologous mutations. WES revealed missense mutations in that were inherited in an autosomal recessive manner. CTF18, encoded by the gene, is a component of a secondary clamp loader, which is primarily thought to function by promoting DNA replication. We determined that the patient's variants in (CTF18 R751W and E851Q) were damaging to function and severely attenuated the capacity of CTF18 to support hematopoiesis and lymphoid development, strongly suggesting that they were responsible for his T lymphopenia; however, the function of CTF18 appeared to be unrelated to its role as a clamp loader. DNA-damage, expected when replication is impaired, was not evident by expression profiling in murine mutant hematopoietic stem and progenitor cells (HSPC), nor was development of Ctf18-deficient progenitors rescued by p53 loss. Instead, we observed an expression signature suggesting disruption of HSPC positioning and migration. Indeed, the positioning of HSPC in morphant zebrafish embryos was perturbed, suggesting that HSPC function was impaired through disrupted positioning in hematopoietic organs. Accordingly, we propose that T lymphopenia in our patient resulted from disturbed cell-cell contacts and migration of HSPC, caused by a non-canonical function of CHTF18 in regulating gene expression.

IgA plasmocytes are shown to promote resistance to the immunogenic chemotherapeutic oxaliplatin in prostate cancer mouse models by inhibiting activation of cytotoxic T cells; immunosuppressive plasma cells, which are also found in human-therapy-resistant prostate cancer, are generated in response to TGFβ, and their functionality depends on PD-L1 expression and IL-10 secretion. Tumour resistance to oxaliplatin Oxaliplatin, an immunogenic chemotherapeutic, is effective in aggressive prostate cancer, but as with most other known therapeutics, castration-resistant forms of the cancer become refractory to continued treatment. This study shows that IgA plasmocytes promote resistance to oxaliplatin in prostate cancer mouse models by inhibiting immunogenic tumour cell death and through activation of cytotoxic lymphocytes. Immunosuppressive plasma cells are generated in response to TGFβ, and their functionality depends on the expression of programmed death ligand 1 and interleukin 10. Elimination of these IgA plasmocytes, which also infiltrate human-therapy-resistant prostate cancer, allows cytotoxic-T-cell-dependent eradication of oxaliplatin-treated tumours. Cancer-associated genetic alterations induce expression of tumour antigens that can activate CD8 + cytotoxic T cells (CTLs), but the microenvironment of established tumours promotes immune tolerance through poorly understood mechanisms 1 , 2 . Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers 1 . Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms 3 , 4 . Our previous studies revealed that B cells recruited by the chemokine CXCL13 into prostate cancer tumours promote the progression of castrate-resistant prostate cancer by producing lymphotoxin, which activates an IκB kinase α (IKKα)-BMI1 module in prostate cancer stem cells 5 , 6 . Because castrate-resistant prostate cancer is refractory to most therapies, we examined B cell involvement in the acquisition of chemotherapy resistance. Here we focus on oxaliplatin, an immunogenic chemotherapeutic agent 3 , 4 that is effective in aggressive prostate cancer 7 . We show that mouse B cells modulate the response to low-dose oxaliplatin, which promotes tumour-directed CTL activation by inducing immunogenic cell death. Three different mouse prostate cancer models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGFβ receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.

The liver has remarkable regenerative capacity owing to the boundless proliferative potential of hepatocytes. During liver injury, sustained regeneration must be balanced by mechanisms limiting overgrowth and tumorigenesis. Epithelial plasticity is frequently observed during liver damage and is thought to mediate production of biliary epithelial cells (BECs) or hepatocytes, depending on tissue needs. Here we show that hepatocytes persisting in plastic states are present in virtually all liver injury contexts, representing the predominant outcome of hepatocyte reprogramming rather than their full BEC conversion. By developing tools to trap mouse hepatocytes in plastic states in vivo and using models of regeneration and transplantation, we show that plastic hepatocytes are refractory to proliferation cues from the microenvironment. Unlike terminally differentiated hepatocytes, plastic hepatocytes resist proliferation driven by endogenous oncogenic stimuli. Thus, acquisition of plastic states represents a protective mechanism that constrains hepatocyte proliferation, limiting overgrowth and tumorigenesis during liver disease.

The liver plays an outsized role in oncology. Liver tumors are one of the most frequently found tumors in cancer patients and these arise from either primary or metastatic disease. Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer and the 6th most common cancer type overall, is expected to become the 3rd leading cause of cancer mortality in the US by the year 2030. The liver is also the most common site of distant metastasis from solid tumors. For instance, colorectal cancer (CRC) metastasizes to the liver in two-thirds of cases, and CRC liver metastasis is the leading cause of mortality in these patients. The interplay between inflammation and cancer is unmistakably evident in the liver. In nearly every case, HCC is diagnosed in chronic liver disease (CLD) and cirrhosis background. The consumption of a Western-style high-fat diet is a major risk factor for the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), both of which are becoming more prevalent in parallel with the obesity epidemic. Excessive alcohol intake also contributes significantly to the CLD burden in the form of alcoholic liver disease (ALD). Inflammation is a key component in the development of all CLDs. Additionally, during the development of liver metastasis, pro-inflammatory signaling is crucial in eliminating invading cancer cells but ironically also helps foster a pro-metastatic environment that supports metastatic seeding and colonization. Here we review how Westernized high-fat diets and excessive alcohol intake can influence inflammation within the liver microenvironment, stimulating both primary and metastatic liver tumorigenesis.

dDsk2 is a conserved extraproteasomal ubiquitin receptor that targets ubiquitylated proteins for degradation. Here we report that dDsk2 plays a nonproteolytic function in transcription regulation. dDsk2 interacts with the dHP1c complex, localizes at promoters of developmental genes and is required for transcription. Through the ubiquitin-binding domain, dDsk2 interacts with H2Bub1, a modification that occurs at dHP1c complex-binding sites. H2Bub1 is not required for binding of the complex; however, dDsk2 depletion strongly reduces H2Bub1. Co-depletion of the H2Bub1 deubiquitylase dUbp8/Nonstop suppresses this reduction and rescues expression of target genes. RNA polymerase II is strongly paused at promoters of dHP1c complex target genes and dDsk2 depletion disrupts pausing. Altogether, these results suggest that dDsk2 prevents dUbp8/Nonstop-dependent H2Bub1 deubiquitylation at promoters of dHP1c complex target genes and regulates RNA polymerase II pausing. These results expand the catalogue of nonproteolytic functions of ubiquitin receptors to the epigenetic regulation of chromatin modifications. dDsk2 is a conserved extraproteasomal ubiquitin receptor that targets ubiquitylated proteins for degradation. Here the authors report that dDsk2 regulates RNA polymerase II pausing by preventing H2Bub1 deubiquitylation, suggesting a nonproteolytic function of dDsk2.