Therapeutic targeting of NAMPT and its associated pathways in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a global health challenge that affects more than 700,000 people yearly and has a devastating five-year survival rate at <20%. Current standard of care treatment for HCC showed limited efficacy in patients, driving the need for a more effective targeted therapy. As the major metabolic hub of the body, the liver undergoes tremendous metabolic reprogramming during tumorigenesis. Such remodelling could result in the activation of new metabolic pathways, creating new adaptative mechanisms or cancer-specific dependencies that could be potentially targeted. To uncover clinically relevant cancer-specific metabolic targets, patient derived HCC models were generated and subjected to a high throughput metabolic screening. This revealed therapeutic vulnerability of a subset of HCC towards NAD metabolism and circadian rhythm related pathways, which are commonly dysregulated pathways in HCC. Understanding the mechanistic underpinning this highly unique and understudied pathway in HCC could have potential implications for novel treatment modalities in HCC.Doctor of Philosoph

Comparative Loss-of-Function Screens Reveal ABCE1 as an Essential Cellular Host Factor for Efficient Translation of Paramyxoviridae and Pneumoviridae

International audienceParamyxoviruses and pneumoviruses have similar life cycles and share the respiratory tract as a point of entry. In comparative genome-scale siRNA screens with wild-type-derived measles, mumps, and respiratory syncytial viruses in A549 cells, a human lung adenocarcinoma cell line, we identified vesicular transport, RNA processing pathways, and translation as the top pathways required by all three viruses. As the top hit in the translation pathway, ABCE1, a member of the ATP-binding cassette transporters, was chosen for further study. We found that ABCE1 supports replication of all three viruses, confirming its importance for viruses of both families. More detailed characterization revealed that ABCE1 is specifically required for efficient viral but not general cellular protein synthesis, indicating that paramyxoviral and pneumoviral mRNAs exploit specific translation mechanisms. In addition to providing a novel overview of cellular proteins and pathways that impact these important pathogens, this study highlights the role of ABCE1 as a host factor required for efficient paramyxovirus and pneumovirus translation.IMPORTANCE The Paramyxoviridae and Pneumoviridae families include important human and animal pathogens. To identify common host factors, we performed genome-scale siRNA screens with wild-type-derived measles, mumps, and respiratory syncytial viruses in the same cell line. A comparative bioinformatics analysis yielded different members of the coatomer complex I, translation factors ABCE1 and eIF3A, and several RNA binding proteins as cellular proteins with proviral activity for all three viruses. A more detailed characterization of ABCE1 revealed its essential role for viral protein synthesis. Taken together, these data sets provide new insight into the interactions between paramyxoviruses and pneumoviruses and host cell proteins and constitute a starting point for the development of broadly effective antivirals

Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer

Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for β-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states.Agency for Science, Technology and Research (A*STAR)Ministry of Education (MOE)National Medical Research Council (NMRC)National Research Foundation (NRF)National University of Singapore (NUS), Temasek LaboratoriesPublished versionThis research is supported by the National Medical Research Council, Singapore (OFIRG17may061, OFIRG19nov-0106, OFYIRG18May-0025, and CTGIIT18may0012); National Research Foundation Singapore (NRF-NRFF2015-04, NRFCRP22-2019-0003, NRF-CRP23-2019-0004, and NRFSBP-P4); National Cancer Institute Singapore Yong Siew Yoon Research Grant; Agency for Science, Technology and Research, Singapore (IAF-ICP I1901E0040); National University of Singapore via the Life Sciences Institute (LSI); and the Singapore Ministry of Education under its Research Centers of Excellence initiative