bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2020–03–22
twenty papers selected by
Ralitsa Radostinova Madsen, University College London
  1. Rap1-GTPases control mTORC1 activity by coordinating lysosome organization with amino acid availability.
  2. An oxide transport chain essential for balanced insulin action.
  3. GSK-3-TSC axis governs lysosomal acidification through autophagy and endocytic pathways.
  4. Insulin-Like Growth Factor Binding Protein-5 in Physiology and Disease.
  5. Insulin stimulated GLUT4 translocation - Size is not everything!
  6. Transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation.
  7. The role of metabolic checkpoint regulators in B cell survival and transformation.
  8. Branched-Chain Amino Acids Exacerbate Obesity-Related Hepatic Glucose and Lipid Metabolic Disorders via Attenuating Akt2 Signaling.
  9. Podocyte-specific deletion of tubular sclerosis complex 2 promotes focal segmental glomerulosclerosis and progressive renal failure.
  10. Use of Human Induced Pluripotent Stem Cells and Kidney Organoids To Develop a Cysteamine/mTOR Inhibition Combination Therapy for Cystinosis.
  11. Sugar-Induced Obesity and Insulin Resistance Are Uncoupled from Shortened Survival in Drosophila.
  12. Endothelial Notch signaling controls insulin transport in muscle.
  13. Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo.
  14. Impact of vascular anomalies on the PTEN phenotype in children and young adults.
  15. Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease.
  16. Nutrient Signaling and Lysosome Positioning Crosstalk Through a Multifunctional Protein, Folliculin.
  17. PI3Kinase-p110δ Overexpression Impairs Dendritic Morphogenesis and Increases Dendritic Spine Density.
  18. AKT1 regulates endoplasmic reticula stress and mediates adaptive response of pancreatic β-cells.
  19. Free fatty acid processing diverges in human pathologic insulin resistance conditions.
  20. Infantile macrocephaly and multiple subcutaneous lipomas diagnosed with PTEN hamartoma tumor syndrome: A case report.
  1. Nat Commun. 2020 Mar 17. 11(1): 1416
    Rap1-GTPases control mTORC1 activity by coordinating lysosome organization with amino acid availability.
    Anders P Mutvei, Michal J Nagiec, Jens C Hamann, Sang Gyun Kim, C Theresa Vincent, John Blenis.
      The kinase mTOR complex 1 (mTORC1) promotes cellular growth and is frequently dysregulated in cancers. In response to nutrients, mTORC1 is activated on lysosomes by Rag and Rheb guanosine triphosphatases (GTPases) and drives biosynthetic processes. How limitations in nutrients suppress mTORC1 activity remains poorly understood. We find that when amino acids are limited, the Rap1-GTPases confine lysosomes to the perinuclear region and reduce lysosome abundance, which suppresses mTORC1 signaling. Rap1 activation, which is independent of known amino acid signaling factors, limits the lysosomal surface available for mTORC1 activation. Conversely, Rap1 depletion expands the lysosome population, which markedly increases association between mTORC1 and its lysosome-borne activators, leading to mTORC1 hyperactivity. Taken together, we establish Rap1 as a critical coordinator of the lysosomal system, and propose that aberrant changes in lysosomal surface availability can impact mTORC1 signaling output.
    DOI:  https://doi.org/10.1038/s41467-020-15156-5
  2. Atherosclerosis. 2020 Feb 13. pii: S0021-9150(20)30086-1. [Epub ahead of print]298 42-51
    An oxide transport chain essential for balanced insulin action.
    Xiangdong Wu, Keyang Chen, Kevin Jon Williams.
       BACKGROUND AND AIMS: Patients with overnutrition, obesity, the atherometabolic syndrome, and type 2 diabetes typically develop fatty liver, atherogenic dyslipoproteinemia, hyperglycemia, and hypertension. These features share an unexplained origin - namely, imbalanced insulin action, also called pathway-selective insulin resistance and responsiveness. To control glycemia, these patients require hyperinsulinemia that then overdrives ERK and hepatic de-novo lipogenesis. We previously reported that NADPH oxidase-4 regulates balanced insulin action, but the model appeared incomplete.
    METHODS: We conducted structure-function studies in liver cells to search for additional molecular mediators of balanced insulin action.
    RESULTS: We found that NADPH oxidase-4 is part of a new limb of insulin signaling that we abbreviate "NSAPP" after its five major proteins. The NSAPP pathway is an oxide transport chain that begins when insulin stimulates NADPH oxidase-4 to generate superoxide (O2•-). NADPH oxidase-4 forms a novel, tight complex with superoxide dismutase-3, to efficiently transfer O2•- for quantitative conversion into hydrogen peroxide. The pathway ends when aquaporin-3 channels H2O2 across the plasma membrane to inactivate PTEN. Accordingly, aquaporin-3 forms a novel complex with PTEN in McArdle hepatocytes and in unpassaged human primary hepatic parenchymal cells. Molecular or chemical disruption of any component of the NSAPP chain, from NADPH oxidase-4 up to PTEN, leaves PTEN persistently active, thereby recapitulating the same deadly pattern of imbalanced insulin action seen clinically.
    CONCLUSIONS: The NSAPP pathway functions as a master regulator of balanced insulin action via ERK, PI3K-AKT, and downstream targets of AKT. Unraveling its dysfunction in overnutrition might clarify the molecular cause of the atherometabolic syndrome and type 2 diabetes.
    Keywords:  Atherometabolic syndrome; FOXO1 (forkhead box O1); Insulin; Metabolic regulation; Signal transduction; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2020.02.006
  3. Cell Signal. 2020 Mar 12. pii: S0898-6568(20)30074-7. [Epub ahead of print] 109597
    GSK-3-TSC axis governs lysosomal acidification through autophagy and endocytic pathways.
    Limor Avrahami, Rom Paz, Kristina Dominko, Silva Hecimovic, Cecilia Bucci, Hagit Eldar-Finkelman.
      Impaired lysosomal activity, which results in defective protein processing, waste accumulation, and protein aggregation, is implicated in a number of disease pathologies. Acidification of lysosomes is a crucial process required for lysosome function. Previously we showed that inhibition of glycogen synthase kinase-3 (GSK-3) enhanced lysosomal acidification in both normal and pathological conditions. However, how GSK-3 integrates into the lysosome networking is unknown. Here we show that inhibition of mTORC1 and increased autophagic activity are downstream to GSK-3 inhibition and contribute to lysosomal acidification. Strikingly, lysosomal acidification is also restored by GSK-3 inhibition in the absence of functional autophagy, and, independently of mTORC1. This is facilitated by increased endocytic traffic: We show that GSK-3 inhibition enhanced material internalization, increased recruitment of active Rab5 into endosomes, and increased Rab7/RILP clustering into lysosomes, all processes required for late endosome maturation. Consistently, in cells defective in endocytic traffic caused by either constitutively active Rab5, or, deletion of the Niemann-Pick C1 protein, GSK-3 inhibition could not restore lysosomal acidification. Finally we found that the tuberous sclerosis complex, TSC, is required for lysosomal acidification and is activated by GSK-3 inhibition. Thus, the GSK-3/TSC axis regulates lysosomal acidification via both the autophagic and endocytic pathways. Our study provides new insights into the therapeutic potential of GSK-3 inhibitors in treating pathological conditions associated with impaired cellular clearance.
    Keywords:  Acidification; Autophagy; Endocytosis; GSK-3; GSK-3 inhibitors; L803-mts; Lysosomes; Rab5; Rab7; TSC; mTOR
    DOI:  https://doi.org/10.1016/j.cellsig.2020.109597
  4. Front Endocrinol (Lausanne). 2020 ;11 100
    Insulin-Like Growth Factor Binding Protein-5 in Physiology and Disease.
    Cumming Duan, John B Allard.
      Insulin-like growth factor (IGF) signaling is regulated by a conserved family of IGF binding proteins (IGFBPs) in vertebrates. Among the six distinct types of IGFBPs, IGFBP-5 is the most highly conserved across species and has the broadest range of biological activities. IGFBP-5 is expressed in diverse cell types, and its expression level is regulated by a variety of signaling pathways in different contexts. IGFBP-5 can exert a range of biological actions including prolonging the half-life of IGFs in the circulation, inhibition of IGF signaling by competing with the IGF-1 receptor for ligand binding, concentrating IGFs in certain cells and tissues, and potentiation of IGF signaling by delivery of IGFs to the IGF-1 receptor. IGFBP-5 also has IGF-independent activities and is even detected in the nucleus. Its broad biological activities make IGFBP-5 an excellent representative for understanding IGFBP functions. Despite its evolutionary conservation and numerous biological activities, knockout of IGFBP-5 in mice produced only a negligible phenotype. Recent research has begun to explain this paradox by demonstrating cell type-specific and physiological/pathological context-dependent roles for IGFBP-5. In this review, we survey and discuss what is currently known about IGFBP-5 in normal physiology and human disease. Based on recent in vivo genetic evidence, we suggest that IGFBP-5 is a multifunctional protein with the ability to act as a molecular switch to conditionally regulate IGF signaling.
    Keywords:  AKT; IGF signaling; IGF-dependent; IGF-independent action; PAPP-A; STC; mTOR
    DOI:  https://doi.org/10.3389/fendo.2020.00100
  5. Curr Opin Cell Biol. 2020 Mar 14. pii: S0955-0674(20)30029-6. [Epub ahead of print]65 28-34
    Insulin stimulated GLUT4 translocation - Size is not everything!
    Nia J Bryant, Gwyn W Gould.
      Insulin-regulated trafficking of the facilitative glucose transporter GLUT4 has been studied in many cell types. The translocation of GLUT4 from intracellular membranes to the cell surface is often described as a highly specialised form of membrane traffic restricted to certain cell types such as fat and muscle, which are the major storage depots for insulin-stimulated glucose uptake. Here, we discuss evidence that favours the argument that rather than being restricted to specialised cell types, the machinery through which insulin regulates GLUT4 traffic is present in all cell types. This is an important point as it provides confidence in the use of experimentally tractable model systems to interrogate the trafficking itinerary of GLUT4.
    Keywords:  GLUT4; Translocation
    DOI:  https://doi.org/10.1016/j.ceb.2020.02.006
  6. Proc Natl Acad Sci U S A. 2020 Mar 19. pii: 201914786. [Epub ahead of print]
    Transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation.
    Yong Yi, Deshi Chen, Juan Ao, Wenhua Zhang, Jianqiao Yi, Xiaokun Ren, Junjie Fei, Fengtian Li, Mengmeng Niu, Hu Chen, Yangkun Luo, Zhijun Luo, Zhi-Xiong Jim Xiao.
      AMP-activated protein kinase (AMPK) functions as an energy sensor and is pivotal in maintaining cellular metabolic homeostasis. Numerous studies have shown that down-regulation of AMPK kinase activity or protein stability not only lead to abnormality of metabolism but also contribute to tumor development. However, whether transcription regulation of AMPK plays a critical role in cancer metastasis remains unknown. In this study, we demonstrate that AMPKα1 expression is down-regulated in advanced human breast cancer and is associated with poor clinical outcomes. Transcription of AMPKα1 is inhibited on activation of PI3K and HER2 through ΔNp63α. Ablation of AMPKα1 expression or inhibition of AMPK kinase activity leads to disruption of E-cadherin-mediated cell-cell adhesion in vitro and increased tumor metastasis in vivo. Furthermore, restoration of AMPKα1 expression significantly rescues PI3K/HER2-induced disruption of cell-cell adhesion, cell invasion, and cancer metastasis. Together, these results demonstrate that the transcription control is another layer of AMPK regulation and suggest a critical role for AMPK in regulating cell-cell adhesion and cancer metastasis.
    Keywords:  AMPK; cancer metastasis; cell adhesion; oncogenic signaling; ΔNp63α
    DOI:  https://doi.org/10.1073/pnas.1914786117
  7. Immunol Rev. 2020 Mar 17.
    The role of metabolic checkpoint regulators in B cell survival and transformation.
    Julia Jellusova.
      In response to mitogenic stimulation, B cells activate different pro-anabolic signaling pathways such as c-Myc- and mTORC1-dependent networks to satisfy the energetic demands of biomass synthesis and proliferation. In order to preserve viability and function, cell growth cannot progress unchecked and must be adjusted according to the availability of nutrients. Nutrient-sensing proteins such as AMPK antagonize mTORC1 activity in response to starvation. If pro-anabolic signaling pathways are aberrantly activated, B cells may lack the metabolic capacity to accommodate their energetic needs, which can lead to cell death. On the other hand, metabolic hyperactivation is a salient feature of cancer cells, suggesting that mechanisms exist, which allow B cells to cope with metabolic stress. The aim of this review is to discuss how B cells respond to a mismatch between energy supply and demand and what the consequences are of metabolic dysregulation in normal and malignant B cells.
    Keywords:  B cells; anabolism; autophagy; mTORC1; metabolic stress; senescence
    DOI:  https://doi.org/10.1111/imr.12855
  8. Diabetes. 2020 Mar 17. pii: db190920. [Epub ahead of print]
    Branched-Chain Amino Acids Exacerbate Obesity-Related Hepatic Glucose and Lipid Metabolic Disorders via Attenuating Akt2 Signaling.
    Huishou Zhao, Fuyang Zhang, Dan Sun, Xiong Wang, Xiaomeng Zhang, Jinglong Zhang, Feng Yan, Chong Huang, Huaning Xie, Chen Lin, Yi Liu, Miaomiao Fan, Wenjun Yan, Youhu Chen, Kun Lian, Yueyang Li, Ling Zhang, Shan Wang, Ling Tao.
      Branched chain amino acids (BCAAs) are associated with the progression of obesity-related metabolic disorders, including T2DM and non-alcoholic fatty liver disease. However, whether BCAAs disrupt the homeostasis of hepatic glucose and lipid metabolism remains unknown. In this study, we observed that BCAAs supplementation significantly reduced high-fat (HF) diet-induced hepatic lipid accumulation while increasing the plasma lipid levels and promoting muscular and renal lipid accumulation. Further studies demonstrated that BCAAs supplementation significantly increased hepatic gluconeogenesis and suppressed hepatic lipogenesis in HF diet-induced obese (DIO) mice. These phenotypes resulted from severe attenuation of Akt2 signaling via mTORC1- and mTORC2-dependent pathways. BCAAs/branched-chain α-keto acids (BCKAs) chronically suppressed Akt2 activation through mTORC1 and mTORC2 signaling and promoted Akt2 ubiquitin-proteasome-dependent degradation through the mTORC2 pathway. Moreover, the E3 ligase Mul1 played an essential role in BCAAs/BCKAs-mTORC2-induced Akt2 ubiquitin-dependent degradation. We also demonstrated that BCAAs inhibited hepatic lipogenesis by blocking Akt2/SREBP1/INSIG2a signaling and increased hepatic glycogenesis by regulating Akt2/Foxo1 signaling. Collectively, these data demonstrate that in DIO mice, BCAAs supplementation resulted in serious hepatic metabolic disorder and severe liver insulin resistance: insulin failed to not only suppress gluconeogenesis but also activate lipogenesis. Intervening BCAA metabolism is a potential therapeutic target for severe insulin-resistant disease.
    DOI:  https://doi.org/10.2337/db19-0920
  9. PLoS One. 2020 ;15(3): e0229397
    Podocyte-specific deletion of tubular sclerosis complex 2 promotes focal segmental glomerulosclerosis and progressive renal failure.
    Wakiko Iwata, Hiroyuki Unoki-Kubota, Hideki Kato, Akira Shimizu, Michihiro Matsumoto, Toshiyuki Imasawa, Arisa Igarashi, Kenji Matsumoto, Tetsuo Noda, Yasuo Terauchi, Masaomi Nangaku, Masato Kasuga, Yasushi Kaburagi.
      Obesity can initiate and accelerate the progression of kidney diseases. However, it remains unclear how obesity affects renal dysfunction. Here, we show that a newly generated podocyte-specific tubular sclerosis complex 2 (Tsc2) knockout mouse model (Tsc2Δpodocyte) develops proteinuria and dies due to end-stage renal dysfunction by 10 weeks of age. Tsc2Δpodocyte mice exhibit an increased glomerular size and focal segmental glomerulosclerosis, including podocyte foot process effacement, mesangial sclerosis and proteinaceous casts. Podocytes isolated from Tsc2Δpodocyte mice show nuclear factor, erythroid derived 2, like 2-mediated increased oxidative stress response on microarray analysis and their autophagic activity is lowered through the mammalian target of rapamycin (mTOR)-unc-51-like kinase 1 pathway. Rapamycin attenuated podocyte dysfunction and extends survival in Tsc2Δpodocyte mice. Additionally, mTOR complex 1 (mTORC1) activity is increased in podocytes of renal biopsy specimens obtained from obese patients with chronic kidney disease. Our work shows that mTORC1 hyperactivation in podocytes leads to severe renal dysfunction and that inhibition of mTORC1 activity in podocytes could be a key therapeutic target for obesity-related kidney diseases.
    DOI:  https://doi.org/10.1371/journal.pone.0229397
  10. J Am Soc Nephrol. 2020 Mar 20. pii: ASN.2019070712. [Epub ahead of print]
    Use of Human Induced Pluripotent Stem Cells and Kidney Organoids To Develop a Cysteamine/mTOR Inhibition Combination Therapy for Cystinosis.
    Jennifer A Hollywood, Aneta Przepiorski, Randall F D'Souza, Sreevalsan Sreebhavan, Ernst J Wolvetang, Patrick T Harrison, Alan J Davidson, Teresa M Holm.
       BACKGROUND: Mutations in CTNS-a gene encoding the cystine transporter cystinosin-cause the rare, autosomal, recessive, lysosomal-storage disease cystinosis. Research has also implicated cystinosin in modulating the mTORC1 pathway, which serves as a core regulator of cellular metabolism, proliferation, survival, and autophagy. In its severest form, cystinosis is characterized by cystine accumulation, renal proximal tubule dysfunction, and kidney failure. Because treatment with the cystine-depleting drug cysteamine only slows disease progression, there is an urgent need for better treatments.
    METHODS: To address a lack of good human-based cell culture models for studying cystinosis, we generated the first human induced pluripotent stem cell (iPSC) and kidney organoid models of the disorder. We used a variety of techniques to examine hallmarks of cystinosis-including cystine accumulation, lysosome size, the autophagy pathway, and apoptosis-and performed RNA sequencing on isogenic lines to identify differentially expressed genes in the cystinosis models compared with controls.
    RESULTS: Compared with controls, these cystinosis models exhibit elevated cystine levels, increased apoptosis, and defective basal autophagy. Cysteamine treatment ameliorates this phenotype, except for abnormalities in apoptosis and basal autophagy. We found that treatment with everolimus, an inhibitor of the mTOR pathway, reduces the number of large lysosomes, decreases apoptosis, and activates autophagy, but it does not rescue the defect in cystine loading. However, dual treatment of cystinotic iPSCs or kidney organoids with cysteamine and everolimus corrects all of the observed phenotypic abnormalities.
    CONCLUSIONS: These observations suggest that combination therapy with a cystine-depleting drug such as cysteamine and an mTOR pathway inhibitor such as everolimus has potential to improve treatment of cystinosis.
    Keywords:  cystinosis; induced pluripotent stem cells; kidney disease; kidney organoids; new treatments
    DOI:  https://doi.org/10.1681/ASN.2019070712
  11. Cell Metab. 2020 Mar 16. pii: S1550-4131(20)30075-9. [Epub ahead of print]
    Sugar-Induced Obesity and Insulin Resistance Are Uncoupled from Shortened Survival in Drosophila.
    Esther van Dam, Lucie A G van Leeuwen, Eliano Dos Santos, Joel James, Lena Best, Claudia Lennicke, Alec J Vincent, Georgios Marinos, Andrea Foley, Marcela Buricova, Joao B Mokochinski, Holger B Kramer, Wolfgang Lieb, Matthias Laudes, Andre Franke, Christoph Kaleta, Helena M Cochemé.
      High-sugar diets cause thirst, obesity, and metabolic dysregulation, leading to diseases including type 2 diabetes and shortened lifespan. However, the impact of obesity and water imbalance on health and survival is complex and difficult to disentangle. Here, we show that high sugar induces dehydration in adult Drosophila, and water supplementation fully rescues their lifespan. Conversely, the metabolic defects are water-independent, showing uncoupling between sugar-induced obesity and insulin resistance with reduced survival in vivo. High-sugar diets promote accumulation of uric acid, an end-product of purine catabolism, and the formation of renal stones, a process aggravated by dehydration and physiological acidification. Importantly, regulating uric acid production impacts on lifespan in a water-dependent manner. Furthermore, metabolomics analysis in a human cohort reveals that dietary sugar intake strongly predicts circulating purine levels. Our model explains the pathophysiology of high-sugar diets independently of obesity and insulin resistance and highlights purine metabolism as a pro-longevity target.
    Keywords:  Drosophila; aging; diabetes; high-sugar diet; obesity; purine catabolism; uric acid; water imbalance
    DOI:  https://doi.org/10.1016/j.cmet.2020.02.016
  12. EMBO Mol Med. 2020 Mar 18. e09271
    Endothelial Notch signaling controls insulin transport in muscle.
    Sana S Hasan, Markus Jabs, Jacqueline Taylor, Lena Wiedmann, Thomas Leibing, Viola Nordström, Giuseppina Federico, Leticia P Roma, Christopher Carlein, Gretchen Wolff, Bilgen Ekim-Üstünel, Maik Brune, Iris Moll, Fabian Tetzlaff, Hermann-Josef Gröne, Thomas Fleming, Cyrill Géraud, Stephan Herzig, Peter P Nawroth, Andreas Fischer.
      The role of the endothelium is not just limited to acting as an inert barrier for facilitating blood transport. Endothelial cells (ECs), through expression of a repertoire of angiocrine molecules, regulate metabolic demands in an organ-specific manner. Insulin flux across the endothelium to muscle cells is a rate-limiting process influencing insulin-mediated lowering of blood glucose. Here, we demonstrate that Notch signaling in ECs regulates insulin transport to muscle. Notch signaling activity was higher in ECs isolated from obese mice compared to non-obese. Sustained Notch signaling in ECs lowered insulin sensitivity and increased blood glucose levels. On the contrary, EC-specific inhibition of Notch signaling increased insulin sensitivity and improved glucose tolerance and glucose uptake in muscle in a high-fat diet-induced insulin resistance model. This was associated with increased transcription of Cav1, Cav2, and Cavin1, higher number of caveolae in ECs, and insulin uptake rates, as well as increased microvessel density. These data imply that Notch signaling in the endothelium actively controls insulin sensitivity and glucose homeostasis and may therefore represent a therapeutic target for diabetes.
    Keywords:  Notch signaling; caveolae; endothelial cell; insulin transport; muscle
    DOI:  https://doi.org/10.15252/emmm.201809271
  13. Cancers (Basel). 2020 Mar 14. pii: E690. [Epub ahead of print]12(3):
    Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo.
    Nicholas R Hum, Aimy Sebastian, Sean F Gilmore, Wei He, Kelly A Martin, Aubree Hinckley, Karen R Dubbin, Monica L Moya, Elizabeth K Wheeler, Matthew A Coleman, Gabriela G Loots.
      Current pre-clinical models of cancer fail to recapitulate the cancer cell behavior in primary tumors primarily because of the lack of a deeper understanding of the effects that the microenvironment has on cancer cell phenotype. Transcriptomic profiling of 4T1 murine mammary carcinoma cells from 2D and 3D cultures, subcutaneous or orthotopic allografts (from immunocompetent or immunodeficient mice), as well as ex vivo tumoroids, revealed differences in molecular signatures including altered expression of genes involved in cell cycle progression, cell signaling and extracellular matrix remodeling. The 3D culture platforms had more in vivo-like transcriptional profiles than 2D cultures. In vivo tumors had more cells undergoing epithelial-to-mesenchymal transition (EMT) while in vitro cultures had cells residing primarily in an epithelial or mesenchymal state. Ex vivo tumoroids incorporated aspects of in vivo and in vitro culturing, retaining higher abundance of cells undergoing EMT while shifting cancer cell fate towards a more mesenchymal state. Cellular heterogeneity surveyed by scRNA-seq revealed that ex vivo tumoroids, while rapidly expanding cancer and fibroblast populations, lose a significant proportion of immune components. This study emphasizes the need to improve in vitro culture systems and preserve syngeneic-like tumor composition by maintaining similar EMT heterogeneity as well as inclusion of stromal subpopulations.
    Keywords:  4T1; EMT; PDX; RNA-seq; TNBC; monolayer culture; single-cell RNA-seq; spheroid; syngeneic culture; tumoroid
    DOI:  https://doi.org/10.3390/cancers12030690
  14. Pediatr Blood Cancer. 2020 Mar 20. e28258
    Impact of vascular anomalies on the PTEN phenotype in children and young adults.
    Arun Gurunathan, Kiersten Ricci, Ionela Iacobas, Surya P Rednam, Katie Wusik, Lin Fei, Adrienne M Hammilll.
      Germline PTEN (phosphatase and tensin homolog) mutations lead to inappropriate cell survival and growth, and a predisposition to multiple cancers. Some patients also have vascular anomalies (VAs), and it is unclear whether these patients have different phenotypes or oncologic risks. We conducted a two-institution retrospective cohort study to better understand the phenotypes of children and young adults with PTEN mutations, and to compare individuals with VA to those without. Almost half of the patients had thyroid tumors and nearly one quarter developed gastrointestinal tumors before 30 years of age. The presence of VA was positively associated with bulky overgrowth but did not appear to modify oncologic risk.
    Keywords:  PTEN; cancer predisposition; overgrowth; vascular anomaly; vascular malformation
    DOI:  https://doi.org/10.1002/pbc.28258
  15. Proc Natl Acad Sci U S A. 2020 Mar 16. pii: 201922344. [Epub ahead of print]
    Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease.
    Panu K Luukkonen, Sylvie Dufour, Kun Lyu, Xian-Man Zhang, Antti Hakkarainen, Tiina E Lehtimäki, Gary W Cline, Kitt Falk Petersen, Gerald I Shulman, Hannele Yki-Järvinen.
      Weight loss by ketogenic diet (KD) has gained popularity in management of nonalcoholic fatty liver disease (NAFLD). KD rapidly reverses NAFLD and insulin resistance despite increasing circulating nonesterified fatty acids (NEFA), the main substrate for synthesis of intrahepatic triglycerides (IHTG). To explore the underlying mechanism, we quantified hepatic mitochondrial fluxes and their regulators in humans by using positional isotopomer NMR tracer analysis. Ten overweight/obese subjects received stable isotope infusions of: [D7]glucose, [13C4]β-hydroxybutyrate and [3-13C]lactate before and after a 6-d KD. IHTG was determined by proton magnetic resonance spectroscopy (1H-MRS). The KD diet decreased IHTG by 31% in the face of a 3% decrease in body weight and decreased hepatic insulin resistance (-58%) despite an increase in NEFA concentrations (+35%). These changes were attributed to increased net hydrolysis of IHTG and partitioning of the resulting fatty acids toward ketogenesis (+232%) due to reductions in serum insulin concentrations (-53%) and hepatic citrate synthase flux (-38%), respectively. The former was attributed to decreased hepatic insulin resistance and the latter to increased hepatic mitochondrial redox state (+167%) and decreased plasma leptin (-45%) and triiodothyronine (-21%) concentrations. These data demonstrate heretofore undescribed adaptations underlying the reversal of NAFLD by KD: That is, markedly altered hepatic mitochondrial fluxes and redox state to promote ketogenesis rather than synthesis of IHTG.
    Keywords:  carbohydrate restriction; citrate synthase; insulin resistance; pyruvate carboxylase; redox
    DOI:  https://doi.org/10.1073/pnas.1922344117
  16. Front Cell Dev Biol. 2020 ;8 108
    Nutrient Signaling and Lysosome Positioning Crosstalk Through a Multifunctional Protein, Folliculin.
    Natàlia de Martín Garrido, Christopher H S Aylett.
      FLCN was identified as the gene responsible for Birt-Hogg-Dubé (BHD) syndrome, a hereditary syndrome associated with the appearance of familiar renal oncocytomas. Most mutations affecting FLCN result in the truncation of the protein, and therefore loss of its associated functions, as typical for a tumor suppressor. FLCN encodes the protein folliculin (FLCN), which is involved in numerous biological processes; mutations affecting this protein thus lead to different phenotypes depending on the cellular context. FLCN forms complexes with two large interacting proteins, FNIP1 and FNIP2. Structural studies have shown that both FLCN and FNIPs contain longin and differentially expressed in normal versus neoplastic cells (DENN) domains, typically involved in the regulation of small GTPases. Accordingly, functional studies show that FLCN regulates both the Rag and the Rab GTPases depending on nutrient availability, which are respectively involved in the mTORC1 pathway and lysosomal positioning. Although recent structural studies shed light on the precise mechanism by which FLCN regulates the Rag GTPases, which in turn regulate mTORC1, how FLCN regulates membrane trafficking through the Rab GTPases or the significance of the intriguing FLCN-FNIP-AMPK complex formation are questions that still remain unanswered. We discuss the recent progress in our understanding of FLCN regulation of both growth signaling and lysosomal positioning, as well as future approaches to establish detailed mechanisms to explain the disparate phenotypes caused by the loss of FLCN function and the development of BHD-associated and other tumors.
    Keywords:  Rab GTPases; Rag GTPases; folliculin; lysosome positioning; mTORC1; nutrient signaling
    DOI:  https://doi.org/10.3389/fcell.2020.00108
  17. Front Mol Neurosci. 2020 ;13 29
    PI3Kinase-p110δ Overexpression Impairs Dendritic Morphogenesis and Increases Dendritic Spine Density.
    Veronica L Hood, Clare Paterson, Amanda J Law.
      Activity and expression of the phosphoinositide 3-kinase (PI3K) catalytic isoform, PIK3CD/p110δ, is increased in schizophrenia, autism, and intellectual delay and pro-cognitive preclinical efficacy of p110δ-inhibition has been demonstrated in pharmacological, genetic, and developmental rodent models of psychiatric disorders. Although PI3K signaling has been implicated in the development and function of neurons and glia; isoform-specific roles of the individual PI3Ks are less clear and the biological effects of increased p110δ on neuronal development are unknown. Since the pathobiological direction of p110δ changes in neurodevelopmental disorders are increased expression and activity, we hypothesized that overexpression of p110δ would impact measures of neuronal development and maturation relevant to connectivity and synaptic transmission. p110δ overexpression in primary rat hippocampal cultures significantly reduced dendritic morphogenesis and arborization and increased immature and mature dendritic spine densities, without impacting cell viability, soma size, or axon length. Together, our novel findings demonstrate the importance of homeostatic regulation of the p110δ isoform for normative neuronal development and highlight a potential pathophysiological mechanism of association to disorders of neurodevelopment.
    Keywords:  PI3K; PIK3CD; autism; dendrite; p110δ; schizophrenia; synapse
    DOI:  https://doi.org/10.3389/fnmol.2020.00029
  18. Mol Cell Biol. 2020 Mar 16. pii: MCB.00031-20. [Epub ahead of print]
    AKT1 regulates endoplasmic reticula stress and mediates adaptive response of pancreatic β-cells.
    Zhechu Peng, Richa Aggarwal, Ni Zeng, Lina He, Eileen X Stiles, Anketse Debebe, Jingyu Chen, Chien-Yu Chen, Bangyan L Stiles.
      Isoforms of protein kinase B (also known as AKT) play important roles in mediating insulin and growth factor signals. Previous studies have suggested that the AKT2 isoform is critical for insulin regulated glucose metabolism while the role of the AKT1 isoform remains less clear. This study focuses on the effects of AKT1 on the adaptive response of pancreatic β-cells. Using a mouse model with inducible β-cell specific deletion of Akt1 gene (βA1KO mice), we showed that AKT1 is involved in high fat diet (HFD) induced growth and survival of β-cells but is unnecessary for them to maintain a population in the absence of metabolic stress. When unchallenged, βA1KO mice presented the same metabolic profile and β-cell phenotype as the control mice with intact Akt1 genes. When metabolic stress was induced by HFD, β-cells in control mice with intact Akt1 proliferated as a compensatory mechanism for metabolic overload. Similar effects were not observed in βA1KO mice. We further demonstrated that AKT1 protein deficiency caused ER stress and potentiated β-cells to undergo apoptosis. Our results revealed that AKT1 protein loss led to induction of eIF2a signaling and ER stress markers under normal chow fed condition, indicating chronic low-level ER stress. Together, these data established a role of AKT1 as a growth and survival factor for adaptive β -cell response and suggest that ER stress induction may be responsible for this effect of AKT1.
    DOI:  https://doi.org/10.1128/MCB.00031-20
  19. J Clin Invest. 2020 Mar 19. pii: 135431. [Epub ahead of print]
    Free fatty acid processing diverges in human pathologic insulin resistance conditions.
    Hilal Sekizkardes, Stephanie T Chung, Shaji Chacko, Morey Haymond, Megan Startzell, Mary Walter, Peter J Walter, Marissa Lightbourne, Rebecca J Brown.
       BACKGROUND: Post-receptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptor-level IR (e.g. insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined four pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis.
    METHODS: Cross-sectional study of severe, receptor IR (INSR, n=7), versus post-receptor IR that was severe (lipodystrophy, n=14), moderate (type 2 diabetes [T2D], n=9) or mild (obesity, n=8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma β-hydroxybutyrate) were measured.
    RESULTS: Lipolysis was 2-3-fold higher in INSR versus all other groups, and HGP 2-fold higher in INSR and lipodystrophy versus T2D and obesity (p<0.001) suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, ~77%, versus 52-59% in other groups (p=0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5 [0.1-0.5]), in contrast to lipodystrophy (10.6 [2.8-17.1], p<0.0001). β-hydroxybutyrate was 2-7-fold higher in INSR versus all other groups (p<0.0001) consistent with higher hepatic fat oxidation.
    CONCLUSION: These data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and post-receptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in post-receptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis.
    TRIAL REGISTRATION: ClinicalTrials.gov NCT01778556; NCT00001987; NCT02457897Funding. NIDDK, USDA ARS 58-3092-5-001.
    Keywords:  Adipose tissue; Endocrinology; Glucose metabolism; Insulin
    DOI:  https://doi.org/10.1172/JCI135431
  20. Mol Clin Oncol. 2020 Apr;12(4): 329-335
    Infantile macrocephaly and multiple subcutaneous lipomas diagnosed with PTEN hamartoma tumor syndrome: A case report.
    Yuka Yotsumoto, Atsuko Harada, Jiro Tsugawa, Yoshihiro Ikura, Hidetsuna Utsunomiya, Satoko Miyatake, Naomichi Matsumoto, Yonehiro Kanemura, Tomoko Hashimoto-Tamaoki.
      A heterozygous loss-of-function mutation of the PTEN gene, one of the tumor suppressor genes, causes a wide variety of disorders, ranging from macrocephaly/autism syndrome to PTEN hamartoma tumor syndrome, including Cowden disease that causes thyroid and breast cancer mainly in the adolescence and young adult generation. An 8-month-old male infant with simple macrocephaly developed a café-au-lait spot and two subcutaneous tumors at the age of 1 year. One of the tumors developed rapidly was resected at the age of 1 year and 9 months and identified as benign lipoma. From the age of 2 years, the patient often threw a tantrum. At the age of 2 years and 9 months, a pathogenic germline mutation was identified in the PTEN gene (NM_000314.7), c.195C>A, p.Y65* in the form of a heterozygous germline variant. Developmental delay was noted but no tumors were found in the thyroid gland and breasts. Immunohistochemistry for PTEN in the resected lipoma demonstrated that the PTEN expression pattern was similar to that in a subcutaneous adipose tissue from a normal subject, suggesting that two-hit was not likely involved in the rapid growth of this lipoma. At the age of 5 years, the patient was diagnosed with autism spectrum disorders with moderate developmental delay. A long-term follow-up is underway to examine developmental changes in psychomotor disorders and possible tumor formation.
    Keywords:  Cowden syndrome; PTEN; PTEN hamartoma tumor syndrome; autism spectrum disorder; lipoma; macrocephaly
    DOI:  https://doi.org/10.3892/mco.2020.1988
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