Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver

Hepatocellular carcinoma (HCC) is driven by repeated rounds of inflammation, leading to fibrosis, cirrhosis, and, ultimately, cancer. A critical step in HCC formation is the transition from fibrosis to cirrhosis, which is associated with a change in the liver parenchyma called ductular reaction. Here, we report a genetically engineered mouse model of HCC driven by loss of macroautophagy and hemizygosity of phosphatase and tensin homolog, which develops HCC involving ductular reaction. We show through lineage tracing that, following loss of autophagy, mature hepatocytes dedifferentiate into biliary-like liver progenitor cells (ductular reaction), giving rise to HCC. Furthermore, this change is associated with deregulation of yes-associated protein and transcriptional coactivator with PDZ-binding motif transcription factors, and the combined, but not individual, deletion of these factors completely reverses the dedifferentiation capacity and tumorigenesis. These findings therefore increase our understanding of the cell of origin of HCC development and highlight new potential points for therapeutic intervention

DRAMs and autophagy: a family affair

Macroautophagy/autophagy is a conserved catabolic process that delivers intracellular materials to lysosomes for degradation. This process promotes cell survival by maintaining cellular homeostasis and supplying substrates to produce energy during nutrient-deprived conditions. DRAM1 (DNA damage regulated autophagy modulator 1) is involved in DNA-damage-induced autophagy and belongs to an evolutionarily conserved protein family, which contains five members in human. Our recent study provides the initial characterization of the last two members of the DRAM family in autophagy regulation. Our findings revealed that TMEM150C/DRAM4 (transmembrane protein 150C) and TMEM150A/DRAM5 are nutrient-responsive members of the DRAM family that manifest interconnected roles in modulating the autophagic flux and cell survival under nutrient-deprived conditions. Abbreviations DRAM1: DNA damage regulated autophagy modulator 1 EBSS: Earle’s balanced salt solution MAP1LC3/LC3: Microtubule associated protein 1 light chain

Mannose impairs tumour growth and enhances chemotherapy

It is now well established that tumours undergo changes in cellular metabolism1. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake2, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types