bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2020–03–15
24 papers selected by
Ralitsa Radostinova Madsen, University College London
  1. mTOR complex 2 is an integrator of cancer metabolism and epigenetics.
  2. Spatiotemporal gating of SIRT1 functions by O-GlcNAcylation is essential for liver metabolic switching and prevents hyperglycemia.
  3. PIK3CA and p53 mutations promote 4NQO-initated head and neck tumor progression and metastasis in mice.
  4. Engineering orthogonal, plasma membrane-specific SLIPT systems for multiplexed chemical control of signaling pathways in living single cells.
  5. Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver.
  6. A signaling hub of insulin receptor, dystrophin glycoprotein complex and plakoglobin regulates muscle size.
  7. CLUH granules coordinate translation of mitochondrial proteins with mTORC1 signaling and mitophagy.
  8. Lineage plasticity in cancer: a shared pathway of therapeutic resistance.
  9. Mechanistic insights of adipocyte metabolism in regulating breast cancer progression.
  10. mTORC1 Deficiency Modifies Volume Homeostatic Responses to Dietary Sodium in a Sex-Specific Manner.
  11. Clinical and molecular aspects of PTEN mutations in 10 pediatric patients.
  12. The effectiveness of Sirolimus treatment in two rare disorders with nonketotic hypoinsulinemic hypoglycemia: The role of mTOR pathway
  13. Model Informed Drug Development for Everolimus Dosing Selection in Pediatric Infant Patients.
  14. Proteomic and transcriptomic profiling of Pten gene-knockout mouse model of prostate cancer.
  15. A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation.
  16. Multi-omics Analysis of the Intermittent Fasting Response in Mice Identifies an Unexpected Role for HNF4α.
  17. Cancer associated fibroblast FAK regulates malignant cell metabolism.
  18. Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study.
  19. Transient and late-life rapamycin for healthspan extension.
  20. MYC Dysregulates Mitosis, Revealing Cancer Vulnerabilities.
  21. Metabolic Health, Insulin, and Breast Cancer: Why Oncologists Should Care About Insulin.
  22. VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1.
  23. Lipid droplets, bioenergetic fluxes, and metabolic flexibility.
  24. Brain morphological analysis in PTEN hamartoma tumor syndrome.
  1. Cancer Lett. 2020 Mar 04. pii: S0304-3835(20)30118-X. [Epub ahead of print]
    mTOR complex 2 is an integrator of cancer metabolism and epigenetics.
    Kenta Masui, Mio Harachi, Webster K Cavenee, Paul S Mischel, Noriyuki Shibata.
      Metabolic reprogramming is a central hallmark of cancer and is driven by abnormalites of oncogenes and tumor suppressors. This enables tumor cells to obtain the macromolecular precursors and energy needed for rapid tumor growth. Accelerated metabolism also translates into cancer cell aggression through epigenetic changes. The aberrant signaling cascades activated by oncogenes coordinate metabolic reprogramming with epigenetic shifts and subsequent global transcriptional changes through the dysregulation of rate-limiting metabolic enzymes as well as by facilitating the production of intermediary metabolites. As the landscape of cancer cell metabolism has been elucidated, it is now time for this knowledge to be translated into benefit for patients. Here we review the recently identified central regulatory role for mechanistic/mammalian target of rapamycin complex 2 (mTORC2), a downstream effector of many cancer-causing mutations, in reprogramming the metabolic and epigenetic landscape. This leads to tumor cell survival and cancer drug resistance.
    Keywords:  histone acetylation; iron metabolism; mTOR complex; metabolic reprogramming; microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2020.03.001
  2. Proc Natl Acad Sci U S A. 2020 Mar 09. pii: 201909943. [Epub ahead of print]
    Spatiotemporal gating of SIRT1 functions by O-GlcNAcylation is essential for liver metabolic switching and prevents hyperglycemia.
    Tandrika Chattopadhyay, Babukrishna Maniyadath, Hema P Bagul, Arindam Chakraborty, Namrata Shukla, Srikanth Budnar, Abinaya Rajendran, Arushi Shukla, Siddhesh S Kamat, Ullas Kolthur-Seetharam.
      Inefficient physiological transitions are known to cause metabolic disorders. Therefore, investigating mechanisms that constitute molecular switches in a central metabolic organ like the liver becomes crucial. Specifically, upstream mechanisms that control temporal engagement of transcription factors, which are essential to mediate physiological fed-fast-refed transitions are less understood. SIRT1, a NAD+-dependent deacetylase, is pivotal in regulating hepatic gene expression and has emerged as a key therapeutic target. Despite this, if/how nutrient inputs regulate SIRT1 interactions, stability, and therefore downstream functions are still unknown. Here, we establish nutrient-dependent O-GlcNAcylation of SIRT1, within its N-terminal domain, as a crucial determinant of hepatic functions. Our findings demonstrate that during a fasted-to-refed transition, glycosylation of SIRT1 modulates its interactions with various transcription factors and a nodal cytosolic kinase involved in insulin signaling. Moreover, sustained glycosylation in the fed state causes nuclear exclusion and cytosolic ubiquitin-mediated degradation of SIRT1. This mechanism exerts spatiotemporal control over SIRT1 functions by constituting a previously unknown molecular relay. Of note, loss of SIRT1 glycosylation discomposed these interactions resulting in aberrant gene expression, mitochondrial dysfunctions, and enhanced hepatic gluconeogenesis. Expression of nonglycosylatable SIRT1 in the liver abrogated metabolic flexibility, resulting in systemic insulin resistance, hyperglycemia, and hepatic inflammation, highlighting the physiological costs associated with its overactivation. Conversely, our study also reveals that hyperglycosylation of SIRT1 is associated with aging and high-fat-induced obesity. Thus, we establish that nutrient-dependent glycosylation of SIRT1 is essential to gate its functions and maintain physiological fitness.
    Keywords:  PGC1α; fed–fast cycle; gluconeogenesis; insulin signaling; ubiquitinylation
    DOI:  https://doi.org/10.1073/pnas.1909943117
  3. Mol Cancer Res. 2020 Mar 09. pii: molcanres.0549.2019. [Epub ahead of print]
    PIK3CA and p53 mutations promote 4NQO-initated head and neck tumor progression and metastasis in mice.
    Dario Garcia-Carracedo, Yi Cai, Wanglong Qiu, Kiyoshi Saeki, Richard A Friedman, Andrew Lee, Yinglu Li, Elizabeth M Goldberg, Elias E Stratikopoulos, Ramon Parsons, Chao Lu, Argiris Efstratiadis, Elizabeth M Philipone, Angela J Yoon, Gloria H Su.
      The phosphoinositide 3-kinase (PI3K) signaling pathway is frequently mutated in head and neck squamous cell carcinoma (HNSCC), often via gain-of-function (GOF) mutations in the PIK3CA gene. Here we present novel genetically-engineered mouse models (GEMM) carrying a GOF allele Loxp-STOP-Loxp(LSL)-PIK3CAH1047R (E20) alone or in combination with heterozygous LSL-p53+/R172H (p53) mutation with tissue-specific expression to interrogate the role of oncogenic PIK3CA in transformation of upper aerodigestive track epithelium. We demonstrated that the GOF PIK3CA mutation promoted progression of 4NQO-induced oral squamous cell carcinoma (OSCC) in both E20 single mutant and E20/p53 double mutant mice, with frequent distal metastasis detected only in E20/p53 GEMM. Similar to in human OSCC, loss of p16 was associated with progression of OSCC in these mice. RNA-Seq analyses revealed that among the common genes differentially expressed in primary OSCC cell lines derived from E20, p53, and E20/p53 GEMMs compared to those from the wild-type mice, genes associated with proliferation and cell cycle were predominantly represented, which is consistent with the progressive loss of p16 detected in these GEMMs. Importantly, all of these OSCC primary cell lines exhibited enhanced sensitivity to BYL719 and cisplatin combination treatment in comparison with cisplatin alone in vitro and in vivo, regardless of p53 and/or p16 status. Given the prevalence of mutations in p53 and the PI3K pathways in HNSCC in conjunction with loss of p16 genetically or epigenetically, this universal increased sensitivity to cisplatin and BYL719 combination therapy in cancer cells with PIK3CA mutation represents an opportunity to a subset of HNSCC patients. Implications: Our results suggest that combination therapy of cisplatin and PI3K inhibitor may be worthy of consideration in HNSCC patients with PIK3CA mutation.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-19-0549
  4. ACS Chem Biol. 2020 Mar 12.
    Engineering orthogonal, plasma membrane-specific SLIPT systems for multiplexed chemical control of signaling pathways in living single cells.
    Akinobu Nakamura, Choji Oki, Kenya Kato, Satoko Fujinuma, Gembu Maryu, Keiko Kuwata, Tatsuyuki Yoshii, Michiyuki Matsuda, Kazuhiro Aoki, Shinya Tsukiji.
      Most cell behaviors are the outcome of processing information from multiple signals generated upon cell stimulation. Thus, a systematic understanding of cellular systems requires methods that allow the activation of more than one specific signaling molecule or pathway within a cell. However, the construction of tools suitable for such multiplexed signal control remains challenging. In this work, we aimed to develop a platform for chemically manipulating multiple signaling molecules/pathways in living mammalian cells based on self-localizing ligand-induced protein translocation (SLIPT). SLIPT is an emerging chemogenetic tool that controls protein localization and cell signaling using synthetic self-localizing ligands (SLs). Focusing on the inner leaflet of the plasma membrane (PM), where is a hub of intracellular signaling networks, here we present the design and engineering of two new PM-targeted SLIPT systems based on an orthogonal eDHFR and SNAP-tag pair. These systems rapidly induce translocation of eDHFR- and SNAP-tag-fusion proteins specifically to the PM upon addition of the corresponding SL in a time scale of minutes. The combined use of the two systems enables chemically inducible, individual translocation of two distinct proteins in the same cell. In addition, by integrating the orthogonal SLIPT systems with fluorescent reporters, we demonstrate simultaneous multiplexed activation and fluorescence imaging of endogenous ERK and Akt activities in a single cell. Orthogonal PM-specific SLIPT systems provide a powerful new platform for multiplexed chemical signal control in living single cells, offering new opportunities for dissecting cell signaling networks and synthetic cell manipulation.
    DOI:  https://doi.org/10.1021/acschembio.0c00024
  5. Proc Natl Acad Sci U S A. 2020 Mar 10. pii: 201922370. [Epub ahead of print]
    Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver.
    Thiago M Batista, Sezin Dagdeviren, Shannon H Carroll, Weikang Cai, Veronika Y Melnik, Hye Lim Noh, Suchaorn Saengnipanthkul, Jason K Kim, C Ronald Kahn, Richard T Lee.
      Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show that Arrdc3 is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction in Arrdc3 messenger RNA, while, conversely, mice with liver-specific KO of Arrdc3 (L-Arrdc3 KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus, Arrdc3 is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.
    Keywords:  Arrdc3; alpha arrestins; glucose metabolism; insulin action; liver
    DOI:  https://doi.org/10.1073/pnas.1922370117
  6. Nat Commun. 2020 Mar 13. 11(1): 1381
    A signaling hub of insulin receptor, dystrophin glycoprotein complex and plakoglobin regulates muscle size.
    Yara Eid Mutlak, Dina Aweida, Alexandra Volodin, Bar Ayalon, Nitsan Dahan, Anna Parnis, Shenhav Cohen.
      Signaling through the insulin receptor governs central physiological functions related to cell growth and metabolism. Here we show by tandem native protein complex purification approach and super-resolution STED microscopy that insulin receptor activity requires association with the fundamental structural module in muscle, the dystrophin glycoprotein complex (DGC), and the desmosomal component plakoglobin (γ-catenin). The integrity of this high-molecular-mass assembly renders skeletal muscle susceptibility to insulin, because DGC-insulin receptor dissociation by plakoglobin downregulation reduces insulin signaling and causes atrophy. Furthermore, low insulin receptor activity in muscles from transgenic or fasted mice decreases plakoglobin-DGC-insulin receptor content on the plasma membrane, but not when plakoglobin is overexpressed. By masking β-dystroglycan LIR domains, plakoglobin prevents autophagic clearance of plakoglobin-DGC-insulin receptor co-assemblies and maintains their function. Our findings establish DGC as a signaling hub, and provide a possible mechanism for the insulin resistance in Duchenne Muscular Dystrophy, and for the cardiomyopathies seen with plakoglobin mutations.
    DOI:  https://doi.org/10.1038/s41467-020-14895-9
  7. EMBO J. 2020 Mar 09. e102731
    CLUH granules coordinate translation of mitochondrial proteins with mTORC1 signaling and mitophagy.
    David Pla-Martín, Désirée Schatton, Janica L Wiederstein, Marie-Charlotte Marx, Salim Khiati, Marcus Krüger, Elena I Rugarli.
      Mitochondria house anabolic and catabolic processes that must be balanced and adjusted to meet cellular demands. The RNA-binding protein CLUH (clustered mitochondria homolog) binds mRNAs of nuclear-encoded mitochondrial proteins and is highly expressed in the liver, where it regulates metabolic plasticity. Here, we show that in primary hepatocytes, CLUH coalesces in specific ribonucleoprotein particles that define the translational fate of target mRNAs, such as Pcx, Hadha, and Hmgcs2, to match nutrient availability. Moreover, CLUH granules play signaling roles, by recruiting mTOR kinase and the RNA-binding proteins G3BP1 and G3BP2. Upon starvation, CLUH regulates translation of Hmgcs2, involved in ketogenesis, inhibits mTORC1 activation and mitochondrial anabolic pathways, and promotes mitochondrial turnover, thus allowing efficient reprograming of metabolic function. In the absence of CLUH, a mitophagy block causes mitochondrial clustering that is rescued by rapamycin treatment or depletion of G3BP1 and G3BP2. Our data demonstrate that metabolic adaptation of liver mitochondria to nutrient availability depends on a compartmentalized CLUH-dependent post-transcriptional mechanism that controls both mTORC1 and G3BP signaling and ensures survival.
    Keywords:  CLUH; G3BP; RNA metabolism; mTORC1; mitochondria
    DOI:  https://doi.org/10.15252/embj.2019102731
  8. Nat Rev Clin Oncol. 2020 Mar 09.
    Lineage plasticity in cancer: a shared pathway of therapeutic resistance.
    Álvaro Quintanal-Villalonga, Joseph M Chan, Helena A Yu, Dana Pe'er, Charles L Sawyers, Sen Triparna, Charles M Rudin.
      Lineage plasticity, the ability of cells to transition from one committed developmental pathway to another, has been proposed as a source of intratumoural heterogeneity and of tumour adaptation to an adverse tumour microenvironment including exposure to targeted anticancer treatments. Tumour cell conversion into a different histological subtype has been associated with a loss of dependency on the original oncogenic driver, leading to therapeutic resistance. A well-known pathway of lineage plasticity in cancer - the histological transformation of adenocarcinomas to aggressive neuroendocrine derivatives - was initially described in lung cancers harbouring an EGFR mutation, and was subsequently reported in multiple other adenocarcinomas, including prostate cancer in the presence of antiandrogens. Squamous transformation is a subsequently identified and less well-characterized pathway of adenocarcinoma escape from suppressive anticancer therapy. The increased practice of tumour re-biopsy upon disease progression has increased the recognition of these mechanisms of resistance and has improved our understanding of the underlying biology. In this Review, we provide an overview of the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on neuroendocrine transformation in lung and prostate tumours. We discuss the current understanding of the molecular drivers of this phenomenon, emerging management strategies and open questions in the field.
    DOI:  https://doi.org/10.1038/s41571-020-0340-z
  9. Pharmacol Res. 2020 Mar 06. pii: S1043-6618(19)32041-9. [Epub ahead of print]155 104741
    Mechanistic insights of adipocyte metabolism in regulating breast cancer progression.
    Fuchuang Zhang, Suling Liu.
      Adipocyte account for the largest component in breast tissue. Dysfunctional adipocyte metabolism, such as metaflammation in metabolically abnormal obese patients, will cause hyperplasia and hypertrophy of its constituent adipocytes. Inflamed adipose tissue is one of the biggest risk factors causing breast cancer. Factors linking adipocyte metabolism to breast cancer include dysfunctional secretion of proinflammatory mediators, proangiogenic factors and estrogens. The accumulation of tumor supporting cells and systemic effects, such as insulin resistance, dyslipidemia and oxidative stress, which are caused by abnormal adipocyte metabolism, further contribute to a more aggressive tumor microenvironment and stimulate breast cancer stem cell to influence the development and progression of breast cancer. Here, in this review, we focus on the adipocyte metabolism in regulating breast cancer progression, and discuss the potential targets which can be used for breast cancer therapy.
    Keywords:  Adipocyte; Breast cancer; Breast cancer therapy
    DOI:  https://doi.org/10.1016/j.phrs.2020.104741
  10. Endocrinology. 2020 Mar 10. pii: bqaa041. [Epub ahead of print]
    mTORC1 Deficiency Modifies Volume Homeostatic Responses to Dietary Sodium in a Sex-Specific Manner.
    Danielle L Brooks, Amanda E Garza, Ezgi Caliskan Guzelce, Shadi K Gholami, Thitinan Treesaranuwattana, Stephen Maris, Sanjay Ranjit, Chee Sin Tay, Jessica M Lee, Jose R Romero, Gail K Adler, Luminita H Pojoga, Gordon H Williams.
      Mechanistic target of rapamycin (mTOR) pathway plays a role in features common to both excess salt/aldosterone and cardiovascular/renal diseases. Dietary sodium can upregulate mTORC1 signaling in cardiac and renal tissue, and inhibition of mTOR can prevent aldosterone associated, salt-induced hypertension. The impact of sex and age on mTOR's role in volume homeostasis and the regulation of aldosterone secretion is largely unknown. We hypothesize that both age and sex modify mTOR's interaction with volume homeostatic mechanisms. The activity of three volume homeostatic mechanisms---cardiovascular, renal and hormonal (aldosterone- sodium retaining and brain natriuretic peptide (BNP)- sodium losing)---were assessed in mTORC1 deficient (Raptor +/-) and wildtype male and female littermates at two different ages. The mice were volume stressed by giving a liberal salt (LibS) diet. Raptor +/- mice of both sexes when they aged: 1) reduced their blood pressure; 2) increased left ventricular internal diameter during diastole; 3) decreased renal blood flow; and 4) increased mineralocorticoid receptor expression. Aldosterone levels did not differ by sex in young Raptor +/- mice. However, as they aged, compared to their littermates, aldosterone decreased in males but increased in females. Finally, given the level of Na+ intake, BNP was inappropriately suppressed, but only in Raptor +/- males. These data indicate that Raptor +/- mice, when stressed with a LibS diet, display inappropriate volume homeostatic responses, particularly with aging, and the mechanisms altered, differ by sex.
    Keywords:  Aldosterone; Cardiovascular disease; Raptor; Salt intake; mTOR
    DOI:  https://doi.org/10.1210/endocr/bqaa041
  11. Ann Hum Genet. 2020 Mar 12.
    Clinical and molecular aspects of PTEN mutations in 10 pediatric patients.
    Esra Isik, Ozguc Semih Simsir, Asli Ece Solmaz, Huseyin Onay, Tahir Atik, Ayca Aykut, Asude Durmaz, Ozgur Cogulu, Ferda Ozkinay.
       INTRODUCTION: PTEN gene mutations are responsible for the PTEN hamartoma tumor syndrome (PHTS). In this study, clinical and molecular findings of patients carrying PTEN mutations are presented. Our aim is to contribute to genotype-phenotype correlation and define the most common findings of the syndrome in pediatric patients.
    METHODS AND MATERIALS: Ten molecularly confirmed PHTS patients from seven families were included in the study. All patients were examined by a clinical geneticist. Laboratory test results were obtained from hospital records. Sequencing of PTEN gene was performed. Variant interpretation was done in accordance with 2015 recommendations from the American College of Medical Genetics.
    RESULTS: Macrocephaly was the most common clinical finding, involving all patients. This was followed by skin lesions, neurodevelopmental delay, and pathologic cranial magnetic resonance imaging findings. Seven different heterozygous PTEN gene variants were found in seven families. Four of these were located in exon 5, which has been described as a hot spot area for the PTEN gene. Four mutations were novel. A wide range of phenotypic and genotypic spectra was found in our study group.
    CONCLUSION: Screening of PTEN mutations in patients with macrocephaly is recommended due to an increased risk of cancer. Further cases are needed to make a phenotype-genotype correlation in PHTS.
    Keywords:   PTEN ; Bannayan-Riley-Ruvalcaba syndrome; Cowden syndrome; macrocephaly; mutation spectrum
    DOI:  https://doi.org/10.1111/ahg.12380
  12. J Clin Res Pediatr Endocrinol. 2020 Mar 11.
    The effectiveness of Sirolimus treatment in two rare disorders with nonketotic hypoinsulinemic hypoglycemia: The role of mTOR pathway
    Zeynep Şıklar, Tugba Çetin, Nilgün Çakar, Merih Berberoğlu.
      “Nonketotic-hypoinsulinemic hypoglycemia (NkHH)” is a very rare problem of glucose consumption increase without hyperinsulinism. This disorder has mainly been reported in cases with AKT2 mutation and rarely in cases with PTEN mutation. In cases with PTEN or AKT2 mutation, no effective therapy has been implemented in addition to frequent feeding to counter hypoglycemia. mTOR inhibitor Sirolimus has been used in hyperinsulinemic hypoglycemia that was unresponsive to other medical treatment. In insulin signaling pathway, both AKT2 and PTEN play a role before mTOR. However, the role of Sirolimus on hypoglycemia in AKT2 and PTEN mutations is unknown. Case 1: Six monts old female with AKT2 mutation (c.49G>A (p.E17K) has showed NkHH. Frequent feeding was unsuccesful for treating the hypoglycemia and proptosis has been getting worse. Sirolimus treatment has been started at 3 years of age. Resultantly, blood glucose (BG) levels have been increased to normal levels. Case 2: In a male case with PTEN mutation (p.G132V (c.395G>T), Persistent NkHH has appeared at 16 years of age (fasting BG: 27 mg/dl, fasting insulin1.5 mmol/L, while ketone negative). Sirolimus treatment was started and hypoglycemia was succesfully controlled. NkHH is a very rare and significant disorder which provided some challanges in both diagnosis and treatment. Additionally, AKT2 and also PTEN mutations could lead to NkHH. Sirolimus treatment, by mTOR inhibition, appeared to be effectively controlling the peristent hypoglycemia and could be a lifesaving tool for these kind of disorders.
    Keywords:  AKT2; PTEN; Sirolimus; Hypoglycemia; treatment
    DOI:  https://doi.org/10.4274/jcrpe.galenos.2020.2019.0084
  13. CPT Pharmacometrics Syst Pharmacol. 2020 Mar 09.
    Model Informed Drug Development for Everolimus Dosing Selection in Pediatric Infant Patients.
    Francois Pierre Combes, Heidi J Einolf, Neva Coello, Tycho Heimbach, Handan He, Kai Grosch.
      Everolimus is currently approved in Europe as an adjunctive therapy for patients aged ≥ 2 years with tuberous sclerosis complex (TSC)-associated treatment-refractory partial-onset seizures, based on the EXIST-3 study (NCT01713946) results. As TSC-associated seizures can also affect children aged between 6 months and 2 years, a modeling and simulation (M&S) approach was undertaken to extrapolate exposure (Cmin ) after a dose of 6 mg/m2 , and reduction in seizure frequency (RSF). A physiologically based pharmacokinetic model using Simcyp® was developed to predict Cmin in adult and pediatric patients, which was then used by a population pharmacodynamic model and a linear mixed effect model to predict short-term and long-term efficacy in adults (for validation) and in children, respectively. Based on the results of the M&S study, everolimus at the dose of 6 mg/m2 is anticipated to be an efficacious treatment in children 6 months to 2 years of age (up to 77.8% RSF), with concentrations within the recommended target range.
    Keywords:  everolimus; modeling; seizures; simulation; tuberous sclerosis complex
    DOI:  https://doi.org/10.1002/psp4.12502
  14. Prostate. 2020 Mar 12.
    Proteomic and transcriptomic profiling of Pten gene-knockout mouse model of prostate cancer.
    Jinhui Zhang, Sangyub Kim, Li Li, Christopher J Kemp, Cheng Jiang, Junxuan Lü.
       BACKGROUND: The prostate-specific phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene-conditional knockout (KO) mouse carcinogenesis model is highly desirable for studies of prostate cancer biology and chemoprevention due to its close resemblance of primary molecular defect and many histopathological features of human prostate cancer including androgen response and disease progression from prostatic intraepithelial neoplasia to invasive adenocarcinoma. Here, we profiled the proteome and transcriptome of the Pten-KO mouse prostate tumors for global macromolecular expression alterations for signaling changes and biomarker signatures.
    METHODS: For proteomics, four pairs of whole prostates from tissue-specific conditional knockout Pten-KO mice (12-15 weeks of age) and their respective wild-type littermates housed in the same cages were analyzed by 8-plex isobaric tags for relative and absolute quantitation iTRAQ. For microarray transcriptomic analysis, three additional matched pairs of prostate/tumor specimens from respective mice at 20 to 22 weeks of age were used. Real-time quantitative reverse transcription-polymerase chain reaction was used to verify the trends of protein and RNA expression changes. Gene Set Enrichment Analysis and Ingenuity Pathway Analysis were carried out for bioinformatic characterizations of pathways and networks.
    RESULTS: At the macromolecular level, proteomic and transcriptomic analyses complement and cross-validate to reveal overexpression signatures including inflammation and immune alterations, in particular, neutrophil/myeloid lineage suppressor cell features, chromatin/histones, ion and nutrient transporters, and select glutathione peroxidases and transferases in Pten-KO prostate tumors. Suppressed expression patterns in the Pten-KO prostate tumors included glandular differentiation such as secretory proteins and androgen receptor targets, smooth muscle features, and endoplasmic reticulum stress proteins. Bioinformatic analyses identified immune and inflammation responses as the most profound macromolecular landscape changes, and the predicted key nodal activities through Akt, nuclear factor-kappaB, and P53 in the Pten-KO prostate tumor. Comparison with other genetically modified mouse prostate carcinogenesis models revealed notable molecular distinctions, especially the dominance of immune and inflammation features in the Pten-KO prostate tumors.
    CONCLUSIONS: Our work identified prominent macromolecular signatures and key nodal molecules that help to illuminate the patho- and immunobiology of Pten-loss driven prostate cancer and can facilitate the choice of biomarkers for chemoprevention and interception studies in this clinically relevant mouse prostate cancer model.
    Keywords:  adenocarcinoma; animal model; expression signatures; macromolecular biomarkers; prostate cancer
    DOI:  https://doi.org/10.1002/pros.23972
  15. Cell. 2020 Mar 03. pii: S0092-8674(20)30161-6. [Epub ahead of print]
    A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation.
    Jin Rui Liang, Emily Lingeman, Thao Luong, Saba Ahmed, Matthias Muhar, Truc Nguyen, James A Olzmann, Jacob E Corn.
      Selective autophagy of organelles is critical for cellular differentiation, homeostasis, and organismal health. Autophagy of the ER (ER-phagy) is implicated in human neuropathy but is poorly understood beyond a few autophagosomal receptors and remodelers. By using an ER-phagy reporter and genome-wide CRISPRi screening, we identified 200 high-confidence human ER-phagy factors. Two pathways were unexpectedly required for ER-phagy. First, reduced mitochondrial metabolism represses ER-phagy, which is opposite of general autophagy and is independent of AMPK. Second, ER-localized UFMylation is required for ER-phagy to repress the unfolded protein response via IRE1α. The UFL1 ligase is brought to the ER surface by DDRGK1 to UFMylate RPN1 and RPL26 and preferentially targets ER sheets for degradation, analogous to PINK1-Parkin regulation during mitophagy. Our data provide insight into the cellular logic of ER-phagy, reveal parallels between organelle autophagies, and provide an entry point to the relatively unexplored process of degrading the ER network.
    Keywords:  CRISPR; ER-phagy; UFMylation; autophagy; endoplasmic reticulum; genome-wide screen; organelle turnover; oxidative phosphorylation; post-translational modification
    DOI:  https://doi.org/10.1016/j.cell.2020.02.017
  16. Cell Rep. 2020 Mar 10. pii: S2211-1247(20)30212-6. [Epub ahead of print]30(10): 3566-3582.e4
    Multi-omics Analysis of the Intermittent Fasting Response in Mice Identifies an Unexpected Role for HNF4α.
    Luke Hatchwell, Dylan J Harney, Michelle Cielesh, Kieren Young, Yen Chin Koay, John F O'Sullivan, Mark Larance.
      Every-other-day fasting (EODF) is an effective intervention for the treatment of metabolic disease, including improvements in liver health. But how the liver proteome is reprogrammed by EODF is currently unknown. Here, we use EODF in mice and multi-omics analysis to identify regulated pathways. Many changes in the liver proteome are distinct after EODF and absent after a single fasting bout. Key among these is the simultaneous induction by EODF of de novo lipogenesis and fatty acid oxidation enzymes. Together with activation of oxidative stress defenses, this contributes to the improvements in glucose tolerance and lifespan after EODF. Enrichment analysis shows unexpected downregulation of HNF4α targets by EODF, and we confirm HNF4α inhibition. Suppressed HNF4α targets include bile synthetic enzymes and secreted proteins, such as α1-antitrypsin or inflammatory factors, which reflect EODF phenotypes. Interactive online access is provided to a data resource (https://www.larancelab.com/eodf), which provides a global view of fasting-induced mechanisms in mice.
    Keywords:  HNF4A; SREBP1c; intermittent fasting; liver; metabolomics; plasma; proteomics
    DOI:  https://doi.org/10.1016/j.celrep.2020.02.051
  17. Nat Commun. 2020 Mar 10. 11(1): 1290
    Cancer associated fibroblast FAK regulates malignant cell metabolism.
    Fevzi Demircioglu, Jun Wang, Juliana Candido, Ana S H Costa, Pedro Casado, Beatriz de Luxan Delgado, Louise E Reynolds, Jesus Gomez-Escudero, Emma Newport, Vinothini Rajeeve, Ann-Marie Baker, Marina Roy-Luzarraga, Trevor A Graham, Julie Foster, Yu Wang, James J Campbell, Rajinder Singh, Penglie Zhang, Thomas J Schall, Frances R Balkwill, Jane Sosabowski, Pedro R Cutillas, Christian Frezza, Patricia Sancho, Kairbaan Hodivala-Dilke.
      Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.
    DOI:  https://doi.org/10.1038/s41467-020-15104-3
  18. Br J Cancer. 2020 Mar 09.
    Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study.
    Hans Gelderblom, Robin L Jones, Suzanne George, Claudia Valverde Morales, Charlotte Benson, Jean-Yves Blay, Daniel J Renouf, Toshihiko Doi, Axel Le Cesne, Michael Leahy, Sabine Hertle, Paola Aimone, Ulrike Brandt, Patrick Schӧffski.
       BACKGROUND: The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib.
    METHODS: This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination.
    RESULTS: Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs.
    CONCLUSIONS: Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST.
    TRIAL REGISTRATION NUMBER: NCT01468688.
    DOI:  https://doi.org/10.1038/s41416-020-0769-y
  19. Aging (Albany NY). 2020 Mar 12.
    Transient and late-life rapamycin for healthspan extension.
    Ellen K Quarles, Peter S Rabinovitch.
      
    Keywords:  aging; healthspan; intermittent; persistence; rapamycin
    DOI:  https://doi.org/10.18632/aging.102947
  20. Cell Rep. 2020 Mar 10. pii: S2211-1247(20)30202-3. [Epub ahead of print]30(10): 3368-3382.e7
    MYC Dysregulates Mitosis, Revealing Cancer Vulnerabilities.
    Julia Rohrberg, Daniel Van de Mark, Meelad Amouzgar, Joyce V Lee, Moufida Taileb, Alexandra Corella, Seda Kilinc, Jeremy Williams, Marie-Lena Jokisch, Roman Camarda, Sanjeev Balakrishnan, Rama Shankar, Alicia Zhou, Aaron N Chang, Bin Chen, Hope S Rugo, Sophie Dumont, Andrei Goga.
      Tumors that overexpress the MYC oncogene are frequently aneuploid, a state associated with highly aggressive cancers and tumor evolution. However, how MYC causes aneuploidy is not well understood. Here, we show that MYC overexpression induces mitotic spindle assembly defects and chromosomal instability (CIN) through effects on microtubule nucleation and organization. Attenuating MYC expression reverses mitotic defects, even in established tumor cell lines, indicating an ongoing role for MYC in CIN. MYC reprograms mitotic gene expression, and we identify TPX2 to be permissive for spindle assembly in MYC-high cells. TPX2 depletion blocks mitotic progression, induces cell death, and prevents tumor growth. Further elevating TPX2 expression reduces mitotic defects in MYC-high cells. MYC and TPX2 expression may be useful biomarkers to stratify patients for anti-mitotic therapies. Our studies implicate MYC as a regulator of mitosis and suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.
    Keywords:  CIN; MYC; TNBC; TPX2; chromosomal instability; microtubules; mitosis; mitotic spindle assembly; receptor triple-negative breast cancer; synthetic-lethality
    DOI:  https://doi.org/10.1016/j.celrep.2020.02.041
  21. Front Endocrinol (Lausanne). 2020 ;11 58
    Metabolic Health, Insulin, and Breast Cancer: Why Oncologists Should Care About Insulin.
    Lisa D Yee, Joanne E Mortimer, Rama Natarajan, Eric C Dietze, Victoria L Seewaldt.
      Studies investigating the potential link between adult pre-menopausal obesity [as measured by body mass index (BMI)] and triple-negative breast cancer have been inconsistent. Recent studies show that BMI is not an exact measure of metabolic health; individuals can be obese (BMI > 30 kg/m2) and metabolically healthy or lean (BMI < 25 kg/m2) and metabolically unhealthy. Consequently, there is a need to better understand the molecular signaling pathways that might be activated in individuals that are metabolically unhealthy and how these signaling pathways may drive biologically aggressive breast cancer. One key driver of both type-2 diabetes and cancer is insulin. Insulin is a potent hormone that activates many pathways that drive aggressive breast cancer biology. Here, we review (1) the controversial relationship between obesity and breast cancer, (2) the impact of insulin on organs, subcellular components, and cancer processes, (3) the potential link between insulin-signaling and cancer, and (4) consider time points during breast cancer prevention and treatment where insulin-signaling could be better controlled, with the ultimate goal of improving overall health, optimizing breast cancer prevention, and improving breast cancer survival.
    Keywords:  TNBC (Triple negative breast cancer); breast cancer; insulin; metabolic health; metformin
    DOI:  https://doi.org/10.3389/fendo.2020.00058
  22. Cells. 2020 Mar 11. pii: E687. [Epub ahead of print]9(3):
    VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1.
    Katrin Spengler, Nderim Kryeziu, Silke Große, Alexander S Mosig, Regine Heller.
      AMP-activated protein kinase (AMPK) is activated by vascular endothelial growth factor (VEGF) in endothelial cells and it is significantly involved in VEGF-induced angiogenesis. This study investigates whether the VEGF/AMPK pathway regulates autophagy in endothelial cells and whether this is linked to its pro-angiogenic role. We show that VEGF leads to AMPKα1-dependent phosphorylation of Unc-51-like kinase 1 (ULK1) at its serine residue 556 and to the subsequent phosphorylation of the ULK1 substrate ATG14. This triggers initiation of autophagy as shown by phosphorylation of ATG16L1 and conjugation of the microtubule-associated protein light chain 3B, which indicates autophagosome formation; this is followed by increased autophagic flux measured in the presence of bafilomycin A1 and by reduced expression of the autophagy substrate p62. VEGF-induced autophagy is transient and probably terminated by mechanistic target of rapamycin (mTOR), which is activated by VEGF in a delayed manner. We show that functional autophagy is required for VEGF-induced angiogenesis and may have specific functions in addition to maintaining homeostasis. In line with this, inhibition of autophagy impaired VEGF-mediated formation of the Notch intracellular domain, a critical regulator of angiogenesis. Our study characterizes autophagy induction as a pro-angiogenic function of the VEGF/AMPK pathway and suggests that timely activation of autophagy-initiating pathways may help to initiate angiogenesis.
    Keywords:  AMPK; ULK1; VEGF; angiogenesis; autophagy; mTOR
    DOI:  https://doi.org/10.3390/cells9030687
  23. Semin Cell Dev Biol. 2020 Mar 04. pii: S1084-9521(19)30052-7. [Epub ahead of print]
    Lipid droplets, bioenergetic fluxes, and metabolic flexibility.
    Marta Bosch, Robert G Parton, Albert Pol.
      The capacity of cells and animals to sense and adapt to fluctuations in the availability of energetic substrates is commonly described as metabolic flexibility. This flexibility allows for example the transition from fed to fasting states and to meet the energy demands of exercise in both states. Flexibility is disrupted in pathological conditions such as the metabolic syndrome but in contrast, it is enhanced in some tumours. Lipid droplets (LDs) and mitochondria are key organelles in bioenergetics. In all eukaryotic cells, LDs store and supply essential lipids to produce signalling molecules, membrane building blocks, and the metabolic energy needed to survive during nutrient poor periods. Highly conserved, robust, and regulated mechanisms ensure these bioenergetic fluxes. Although mitochondria are recognized as the epicentre of metabolic flexibility, the contribution of LDs and LD-proteins is often neglected or considered detrimental. Here, we revisit the key roles of LDs during fasting and the intimate collaboration existing with mitochondria when cells sense and respond to fluctuations in substrate availability.
    Keywords:  Bioenergetic fluxes; Fasting; Lipid droplets; Lipids; Metabolic flexibility; Mitochondria
    DOI:  https://doi.org/10.1016/j.semcdb.2020.02.010
  24. Am J Med Genet A. 2020 Mar 12.
    Brain morphological analysis in PTEN hamartoma tumor syndrome.
    Tadashi Shiohama, Jacob Levman, Lana Vasung, Emi Takahashi.
      PTEN hamartoma tumor syndrome (PHTS) is a spectrum of hereditary cancer syndromes caused by germline mutations in PTEN. PHTS is of high interest, because of its high rate of neurological comorbidities including macrocephaly, autism spectrum disorder, and intellectual dysfunction. Since detailed brain morphology and connectivity of PHTS remain unclear, we quantitatively evaluated brain magnetic resonance imaging (MRI) in PHTS. Sixteen structural T1-weighted and 9 diffusion-weighted MR images from 12 PHTS patients and neurotypical controls were used for structural and high-angular resolution diffusion MRI (HARDI) tractography analyses. Mega-corpus callosum was observed in 75%, polymicrogyria in 33%, periventricular white matter lesions in 83%, and heterotopia in 17% of the PHTS participants. While gyrification index and hemispheric cortical thickness showed no significant differences between the two groups, significantly increased global and regional brain volumes, and regionally thicker cortices in PHTS participants were observed. HARDI tractography showed increased volume and length of callosal pathways, increased volume of the arcuate fasciculi (AF), and increased length of the bilateral inferior longitudinal fasciculi (ILF), bilateral inferior fronto-occipital fasciculi (IFOF), and bilateral uncinate fasciculus. A decrease in fractional anisotropy and an increased in apparent diffusion coefficient values of the AF, left ILF, and left IFOF in PHTS.
    Keywords:   PTEN hamartoma tumor syndrome; HARDI; mega corpus callosum; megalencephaly; structural brain MRI
    DOI:  https://doi.org/10.1002/ajmg.a.61532
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