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News Article | April 18, 2017
Site: www.eurekalert.org

Cross-talk between malignant hepatocytes and neighboring progenitor cells signals progenitor cells to become activated, to expand and to maintain them in an undifferentiated state; thus, progenitor cells become oncogenic and contribute to tumourigenesis The malignant transformation of hepatocytes is the origin of most hepatocellular carcinomas, an aggressive type of liver cancer with high mortality rates. But these cells do not act alone. Research conducted by scientists at the Spanish National Cancer Research Centre (CNIO) reveals how hepatocytes "recruit" and "instruct" liver progenitor cells to contribute to the hepatic lesions. "The cellular origin of liver cancer, as well as the origin of tumour heterogeneity, are not clear yet and may be context-dependent," say the authors in the journal Cell Reports. Hepatocytes -the main liver cells- have been considered the main source of hepatocellular carcinomas but the results of this research provide various novel perspectives. "What we are showing here is that hepatic progenitor cells expand during tumorigenesis and, at one point, they become transformed because of oncogenic hepatocyte cross-talk; this makes them participate in liver tumour development in general, and in hepatocellular carcinomas in particular," explains Nabil Djouder, head of the Growth Factors, Nutrients and Cancer Group at the CNIO and main author of the paper. Thanks to an animal model -generated by Djouder and his team- that fairly reproduces the tumour formation process seen in human hepatocarcinogenesis, and to other genetic experiments, the authors have tried to follow the formation of the lesions and to define the histopathology of the various tumours that develop in this organ, whether benign (regenerative nodules, adenomas) or malignant (hepatocellular carcinoma or HCC). "This is what we've seen: oncogenic hepatocytes lead to hepatocellular carcinoma but, in a model that mimics human hepatocarcinogenesis, progenitor cells also participate in liver tumour heterogeneity. They mostly lead to benign tumours but sometimes they can lead to aggressive carcinomas", points out Djouder. In other words, progenitor cells become oncogenic even though they were not initially transformed. Malignant hepatocytes crosstalk and instruct neighbouring progenitor cells to become activated, maintaining them in an undifferentiated state while at the same time proliferating, becoming oncogenic themselves, and contributing to the lesions. This activation occurs, as shown by this study, when the hepatocytes secrete two substances (?-ketoglutarate and galectin-3) that act and transform progenitor cells. "Blocking galectin-3 can block the cross-talk between these cells thereby reducing tumourigenesis", a finding that could have therapeutic implications, explains Djouder.


Buren S.,Nutrients and Cancer Group | Gomes A.L.,Nutrients and Cancer Group | Teijeiro A.,Nutrients and Cancer Group | Fawal M.-A.,Nutrients and Cancer Group | And 7 more authors.
Cancer Cell | Year: 2016

Cancer cells can adapt and survive under low nutrient conditions, but underlying mechanisms remain poorly explored. We demonstrate here that glucose maintains a functional complex between the co-chaperone URI, PP1γ, and OGT, the enzyme catalyzing O-GlcNAcylation. Glucose deprivation induces the activation of PKA, which phosphorylates URI at Ser-371, resulting in PP1γ release and URI-mediated OGT inhibition. Low OGT activity reduces O-GlcNAcylation and promotes c-MYC degradation to maintain cell survival. In the presence of glucose, PP1γ-bound URI increases OGT and c-MYC levels. Accordingly, mice expressing non-phosphorylatable URI (S371A) in hepatocytes exhibit high OGT activity and c-MYC stabilization, accelerating liver tumorigenesis in agreement with c-MYC oncogenic functions. Our work uncovers that URI-regulated OGT confers c-MYC-dependent survival functions in response to glucose fluctuations. © 2016 Elsevier Inc.


Tummala K.S.,Nutrients and Cancer Group | Gomes A.L.,Nutrients and Cancer Group | Yilmaz M.,Nutrients and Cancer Group | Grana O.,Bioinformatics Unit | And 8 more authors.
Cancer Cell | Year: 2014

Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/nicotinamideadenine dinucleotide (NAD+) metabolism, thereby causing DNA damage at early stages of tumorigenesis. Restoring NAD+ pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD+ can be prophylactic or therapeutic in HCC. © 2014 Elsevier Inc.


PubMed | Confocal Microscopy Core Unit, Nutrients and Cancer Group, Spectroscopy and Nuclear Magnetic Resonance Unit and University College London
Type: Journal Article | Journal: Cancer cell | Year: 2016

Cancer cells can adapt and survive under low nutrient conditions, but underlying mechanisms remain poorly explored. We demonstrate here that glucose maintains a functional complex between the co-chaperone URI, PP1, and OGT, the enzyme catalyzing O-GlcNAcylation. Glucose deprivation induces the activation of PKA, which phosphorylates URI at Ser-371, resulting in PP1 release and URI-mediated OGT inhibition. Low OGT activity reduces O-GlcNAcylation and promotes c-MYC degradation to maintain cell survival. In the presence of glucose, PP1-bound URI increases OGT and c-MYC levels. Accordingly, mice expressing non-phosphorylatable URI (S371A) in hepatocytes exhibit high OGT activity and c-MYC stabilization, accelerating liver tumorigenesis in agreement with c-MYC oncogenic functions. Our work uncovers that URI-regulated OGT confers c-MYC-dependent survival functions in response to glucose fluctuations.


Gomes A.L.,Nutrients and Cancer Group | Teijeiro A.,Nutrients and Cancer Group | Buren S.,Nutrients and Cancer Group | Tummala K.S.,Nutrients and Cancer Group | And 5 more authors.
Cancer Cell | Year: 2016

Obesity increases hepatocellular carcinoma (HCC) risks via unknown mediators. We report that hepatic unconventional prefoldin RPB5 interactor (URI) couples nutrient surpluses to inflammation and non-alcoholic steatohepatitis (NASH), a common cause of HCC. URI-induced DNA damage in hepatocytes triggers inflammation via T helper 17 (Th17) lymphocytes and interleukin 17A (IL-17A). This induces white adipose tissue neutrophil infiltration mediating insulin resistance (IR) and fatty acid release, stored in liver as triglycerides, causing NASH. NASH and subsequently HCC are prevented by pharmacological suppression of Th17 cell differentiation, IL-17A blocking antibodies, and genetic ablation of the IL-17A receptor in myeloid cells. Human hepatitis, fatty liver, and viral hepatitis-associated HCC exhibit increased IL-17A correlating positively with steatosis. IL-17A blockers may prevent IR, NASH, and HCC in high-risk patients. © 2016 Elsevier Inc.


PubMed | Johannes Gutenberg University Mainz, Nutrients and Cancer Group, Hospital Universitario Ramon y Cajal and Institute of Oncology Research IOR
Type: Journal Article | Journal: Cancer cell | Year: 2016

Obesity increases hepatocellular carcinoma (HCC) risks via unknown mediators. We report that hepatic unconventional prefoldin RPB5 interactor (URI) couples nutrient surpluses to inflammation and non-alcoholic steatohepatitis (NASH), a common cause of HCC. URI-induced DNA damage in hepatocytes triggers inflammation via T helper 17 (Th17) lymphocytes and interleukin 17A (IL-17A). This induces white adipose tissue neutrophil infiltration mediating insulin resistance (IR) and fatty acid release, stored in liver as triglycerides, causing NASH. NASH and subsequently HCC are prevented by pharmacological suppression of Th17 cell differentiation, IL-17A blocking antibodies, and genetic ablation of the IL-17A receptor in myeloid cells. Human hepatitis, fatty liver, and viral hepatitis-associated HCC exhibit increased IL-17A correlating positively with steatosis. IL-17A blockers may prevent IR, NASH, and HCC in high-risk patients.


Fawal M.-A.,Nutrients and Cancer Group | Brandt M.,Nutrients and Cancer Group | Djouder N.,Nutrients and Cancer Group
Developmental Cell | Year: 2015

Ras homolog enriched in brain (Rheb) is critical formechanistic target of rapamycin complex 1 (mTORC1) activation in response to growth factors and amino acids (AAs). Whereas growth factors inhibit the tuberous sclerosis complex (TSC1-TSC2), a negative Rheb regulator, the role of AAs in Rheb activation remains unknown. Here, we identify microspherule protein 1 (MCRS1) as the essential link between Rheb and mTORC1 activation. MCRS1, in an AA-dependent manner, maintains Rheb at lysosome surfaces, connecting Rheb to mTORC1. MCRS1 suppression in human cancer cells using small interference RNA or mouse embryonic fibroblasts using an inducible-Cre/Lox system reduces mTORC1 activity. MCRS1 depletion promotes Rheb/TSC2 interaction, rendering Rheb inactive and delocalizing it from lysosomes to recycling endocytic vesicles, leading to mTORC1 inactivation. These findings have important implications for signaling mechanisms in various pathologies, including diabetes mellitus and cancer. © 2015 Elsevier Inc.


PubMed | Nutrients and Cancer Group
Type: Journal Article | Journal: Small GTPases | Year: 2016

The small GTPases from the rat sarcoma (Ras) superfamily are a heterogeneous group of proteins of about 21kDa that act as molecular switches, modulating cell signaling pathways and controlling diverse cellular processes. They are active when bound to guanosine triphosphate (GTP) and inactive when bound to guanosine diphosphate (GDP). Ras homolog enriched in brain (Rheb) is a member of the Ras GTPase superfamily and a key activator of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1). We recently determined that microspherule protein 1 (MCRS1) maintains Rheb at lysosomal surfaces in an amino acid-dependent manner. MCRS1 depletion promotes the formation of the GDP-bound form of Rheb, which is then delocalized from the lysosomal platform and transported to endocytic recycling vesicles, leading to mTORC1 inactivation. During this delocalization process, Rheb-GDP remains farnesylated and associated with cellular endomembranes. These findings provide new insights into the regulation of small GTPases, whose activity depends on both their GTP/GDP switch state and their capacity to move between different cellular membrane-bound compartments. Dynamic spatial transport between compartments makes it possible to alter the proximity of small GTPases to their activatory sites depending on the prevailing physiological and cellular conditions.


PubMed | Spectroscopy and Nuclear Magnetic Resonance Unit and, Nutrients and Cancer Group, Cell Signalling and Adhesion Group and Spanish National Cancer Research Center
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2015

Protein kinase B (PKB/Akt) is an important mediator of signals that control various cellular processes including cell survival, growth, proliferation, and metabolism. PKB promotes these processes by phosphorylating many cellular targets, which trigger distinct downstream signaling events. However, how PKB is able to selectively target its substrates to induce specific cellular functions remains elusive. Here we perform a systematic study to dissect mechanisms that regulate intrinsic kinase activity versus mechanisms that specifically regulate activity toward specific substrates. We demonstrate that activation loop phosphorylation and the C-terminal hydrophobic motif are essential for high PKB activity in general. On the other hand, we identify membrane targeting, which for decades has been regarded as an essential step in PKB activation, as a mechanism mainly affecting substrate selectivity. Further, we show that PKB activity in cells can be triggered independently of PI3K by initial hydrophobic motif phosphorylation, presumably through a mechanism analogous to other AGC kinases. Importantly, different modes of PKB activation result in phosphorylation of distinct downstream targets. Our data indicate that specific mechanisms have evolved for signaling nodes, like PKB, to select between various downstream events. Targeting such mechanisms selectively could facilitate the development of therapeutics that might limit toxic side effects.


PubMed | Nutrients and Cancer Group
Type: Journal Article | Journal: Molecular & cellular oncology | Year: 2016

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide yet has limited therapeutic options. We recently demonstrated that inhibition of de novo nicotinamide adenine dinucleotide (NAD(+)) synthesis is responsible for DNA damage, thereby initiating hepatocarcinogenesis. We propose that boosting NAD(+) levels might be used as a prophylactic or therapeutic approach in HCC.

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