bims-pideca 2020-01-26 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2020–01–26
twenty-two papers selected by
Ralitsa Radostinova Madsen, University College London

A Single Bout of One-legged Exercise to Local Exhaustion Decreases Insulin Action in Non-exercised Muscle Leading to Decreased Whole-body Insulin Action.
Metabolic Role of PTEN in Insulin Signaling and Resistance.
Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase Inhibitor Neratinib in HER2-Mutant Cancers.
Dysregulated Expression of Phosphorylated Epidermal Growth Factor Receptor and Phosphatase and Tensin Homologue in Canine Cutaneous Papillomas and Squamous Cell Carcinomas.
Synergistic therapeutic effect of combined PDGFR and SGK1 inhibition in metastasis-initiating cells of breast cancer.
PIK3CA gene mutations in the helical domain correlate with high tumor mutation burden and poor prognosis in metastatic breast carcinomas with late-line therapies.
Linkage Between Obesity Leptin and Breast Cancer.
The single-cell pathology landscape of breast cancer.
Amino Acid Sensing: Architecture of mTORC1 on the Lysosome Surface.
Novel roles of phosphoinositides in signaling, lipid transport, and disease.
Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer.
Proteomic analysis of malignant and benign endometrium according to obesity and insulin-resistance status using Reverse Phase Protein Array.
Stable Isotopes for Tracing Mammalian-Cell Metabolism In Vivo.
Chaperone mediated detection of small molecule target binding in cells.
A Cancer-Specific Ubiquitin Ligase Drives mRNA Alternative Polyadenylation by Ubiquitinating the mRNA 3' End Processing Complex.
Hierarchical clustering of PI3K and MAPK pathway proteins in breast cancer intrinsic subtypes.
Receptor-based mechanism of relative sensing and cell memory in mammalian signaling networks.
Discovery of a Brain Penetrant ATP-competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS disorders.
Medication-induced hyperglycemia: pediatric perspective.
TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells.
Regulation of mTORC1 by Small GTPases in Response to Nutrients.
Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype.

Diabetes. 2020 Jan 23. pii: db191010. [Epub ahead of print]

A Single Bout of One-legged Exercise to Local Exhaustion Decreases Insulin Action in Non-exercised Muscle Leading to Decreased Whole-body Insulin Action.

Dorte E Steenberg, Janne R Hingst, Jesper B Birk, Anette Thorup, Jonas M Kristensen, Kim A Sjøberg, Bente Kiens, Erik A Richter, Jørgen F P Wojtaszewski.

A single bout of exercise enhances insulin action in the exercised muscle. However, not all human studies find that this translates into increased whole-body insulin action, suggesting that insulin action in rested muscle or other organs may be decreased by exercise. To investigate this, eight healthy men underwent a euglycemic hyperinsulinemic clamp on two separate days: One day with prior one-legged knee-extensor exercise to local exhaustion (∼2.5 hours) and another day without exercise. Whole-body glucose disposal was ∼18% lower on the exercise day as compared to the resting day due to decreased (-37%) insulin-stimulated glucose uptake in the non-exercised muscle. Insulin signaling at the level of Akt2 was impaired in the non-exercised muscle on the exercise day suggesting that decreased insulin action in non-exercised muscle may reduce GLUT4 translocation in response to insulin.Thus, the effect of a single bout of exercise on whole-body insulin action depends on the balance between local effects increasing and systemic effects decreasing insulin action. Physiologically, this mechanism may serve to direct glucose into the muscles in need of glycogen replenishment. For insulin-treated patients this complex relationship may explain the difficulties in predicting the adequate insulin dose for maintaining glucose homeostasis following physical activity.

DOI: https://doi.org/10.2337/db19-1010
Cold Spring Harb Perspect Med. 2020 Jan 21. pii: a036137. [Epub ahead of print]

Metabolic Role of PTEN in Insulin Signaling and Resistance.

Yu Zhe Li, Antonio Di Cristofano, Minna Woo.

Phosphatase and tensin homolog (PTEN) is most prominently known for its function in tumorigenesis. However, a metabolic role of PTEN is emerging as a result of its altered expression in type 2 diabetes (T2D), which results in impaired insulin signaling and promotion of insulin resistance during the pathogenesis of T2D. PTEN functions in regulating insulin signaling across different organs have been identified. Through the use of a variety of models, such as tissue-specific knockout (KO) mice and in vitro cell cultures, PTEN's role in regulating insulin action has been elucidated across many cell types. Herein, we will review the recent advancements in the understanding of PTEN's metabolic functions in each of the tissues and cell types that contribute to regulating systemic insulin sensitivity and discuss how PTEN may represent a promising therapeutic strategy for treatment or prevention of T2D.

DOI: https://doi.org/10.1101/cshperspect.a036137
Cancer Cell. 2020 Jan 22. pii: S1535-6108(19)30583-5. [Epub ahead of print]

Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase Inhibitor Neratinib in HER2-Mutant Cancers.

Dhivya R Sudhan, Angel Guerrero-Zotano, Helen Won, Paula González Ericsson, Alberto Servetto, Mariela Huerta-Rosario, Dan Ye, Kyung-Min Lee, Luigi Formisano, Yan Guo, Qi Liu, Lisa N Kinch, Monica Red Brewer, Teresa Dugger, James Koch, Michael J Wick, Richard E Cutler, Alshad S Lalani, Richard Bryce, Alan Auerbach, Ariella B Hanker, Carlos L Arteaga.

  We developed neratinib-resistant HER2-mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Primary and acquired neratinib resistance in HER2-mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1 hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivity to the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimus and neratinib potently arrested the growth of neratinib-resistant xenografts and organoids established from neratinib-resistant PDXs. RNA and whole-exome sequencing revealed RAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencing of HER2-mutant tumors clinically refractory to neratinib, as well as circulating tumor DNA profiling of patients who progressed on neratinib, showed enrichment of genomic alterations that converge to activate the mTOR pathway.

Keywords:  HER2 mutations; TORC1; drug resistance; neratinib; precision oncology

DOI:  https://doi.org/10.1016/j.ccell.2019.12.013
J Comp Pathol. 2020 Jan;pii: S0021-9975(19)30299-3. [Epub ahead of print]174 26-33

Dysregulated Expression of Phosphorylated Epidermal Growth Factor Receptor and Phosphatase and Tensin Homologue in Canine Cutaneous Papillomas and Squamous Cell Carcinomas.

B L Sanz Ressel, A R Massone, C G Barbeito.

  The molecular mechanisms contributing to the development of cutaneous papillomas (CPs) and cutaneous squamous cell carcinomas (CSCCs) are still poorly understood, limiting the ability to identify molecular suitable targets for the development of novel therapies. Persistent activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway is a component of epidermal carcinogenesis in dogs. The present study describes the immunohistochemical expression pattern of two key regulatory molecules involved in the PI3K/Akt/mTOR signalling pathway, phosphorylated epidermal growth factor receptor (pEGFR)Tyr1068 and phosphatase and tensin homologue (PTEN), in samples of normal canine epidermis, CP, preneoplastic epidermis and CSCC using tissue microarrays to determine whether the deregulated activity of these molecules is involved in the pathogenesis of these relevant epidermal tumours of dogs. Expression of pEGFR and PTEN was dysregulated in most samples of CP, preneoplastic epidermis and CSCC. Overexpression of pEGFR, together with decreased expression of PTEN, may facilitate the progression of some canine CPs and CSCCs by deregulation of the key cellular functions in which the PI3K/Akt/mTOR signalling pathway is involved. These findings suggest that the PI3K/Akt/mTOR signalling molecules may be potential therapeutic targets for canine patients with CP and CSCC.

Keywords:  dog; epidermal carcinogenesis; mTOR signalling pathway; tissue microarray

DOI:  https://doi.org/10.1016/j.jcpa.2019.10.005
Cell Death Differ. 2020 Jan 22.

Synergistic therapeutic effect of combined PDGFR and SGK1 inhibition in metastasis-initiating cells of breast cancer.

Lu Yang, Ning Li, Zhicheng Xue, Ling-Rui Liu, Jian Li, Xiaojia Huang, Xinhua Xie, Yutian Zou, Hailin Tang, Xiaoming Xie.

Lack of insight into the identity of the cells that initiate metastasis hampers the development of antimetastatic therapies. Only a tiny fraction of tumor cells termed metastasis-initiating cells (MICs) are able to successfully seed metastases, causing recurrence and therapeutic resistance. Using metastasis models, we describe a subpopulation of MIC derivates from lung metastases that do not have proliferation advantages, express high levels of the PDGF receptors and EMT/stemness-related genes, and are unique in their ability to initiate metastasis. PDGF factors specifically boost the metastatic potential of MIC populations in a PDGFR-dependent manner. However, PDGFR inhibition preferentially suppresses lung metastases, but does not reduce the primary tumor burden. Thus, we found that PDGFR inhibition blocks AKT activation, whereas SGK1, which shares high-similarity kinase domain and overlap substrates with AKT overexpression remains active in MICs. SGK1 and PDGF signaling act in concert to promote metastatic formation, and SGK1 inhibition confers vulnerability to PDGFR inhibitors, also eliciting a powerful antitumor effect. In vivo, SGK1 inhibitors sensitize xenograft tumors to PDGFR-targeted therapies by reducing primary tumor growth and lung metastasis. Consequently, dual inhibition of PDGFR and SGK1 exhibited strong antitumor activities in established breast cancer cell lines in vitro and in vivo. Therefore, this approach not only provides insight into MIC transformation but also aids the design of improved therapeutic strategies for advanced breast cancer.

DOI: https://doi.org/10.1038/s41418-019-0485-4
Aging (Albany NY). 2020 Jan 24. 12

PIK3CA gene mutations in the helical domain correlate with high tumor mutation burden and poor prognosis in metastatic breast carcinomas with late-line therapies.

Yu Tang, Jing Li, Ning Xie, Xiaohong Yang, Liping Liu, Hui Wu, Can Tian, Ying He, Xiao Wang, Qiongzhi He, Zhe-Yu Hu, Quchang Ouyang.

  Nearly half of metastatic breast cancers (MBC) have genetic aberrations in the PI3K/AKT pathway. To investigate the distinct effect of these aberrations on MBC, 193 MBC patients who progressed after the early line (≤2) salvage treatment voluntarily received next generation sequencing (NGS) for a panel of 1,021 genes. 93 (48%) patients had genetic aberrations in the PI3K/AKT pathway. The number of patients with PIK3CA mutations in kinase domain (KD), helical domain (HD) and other domain (OD), were 36 (18.7%), 26 (13.5%), 10 (5.2%), respectively. 21 (10.9%) patients had mutations in PI3K/AKT pathway genes other than PIK3CA (P/A). Compared to PI3K/AKT-wild type (WT) patients, PIK3CA-HD patients had a significantly shorter progression-free survival (PFS) (Logrank p-value < 0.0001). PIK3CA-KD, PIK3CA-OD and other P/A mutations showed similar PFS to WT patients (Logrank p-value = 0.63). PIK3CA-HD patients had a distinct ctDNA mutation profile to patients with other PI3K/AKT mutations. PIK3CA-HD patients had a higher rate of FGFR and NF1 aberrations. In addition, more PIK3CA-HD carriers were TMB-high. Cox regression analyses suggested that PIK3CA-HD mutations, FGFR aberrations and high TMB were all significant risk factors for poor PFS. In conclusion, future research needs to focus more on the treatment strategies targeting PIK3CA-HD mutations.

Keywords:  PIK3CA mutations; ctDNA mutation profile; helical domain; metastatic breast cancers; tumor mutation burden

DOI:  https://doi.org/10.18632/aging.102701
Breast Cancer (Auckl). 2020 ;14 1178223419898458

Linkage Between Obesity Leptin and Breast Cancer.

Manar Fayiz Atoum, Foad Alzoughool, Huda Al-Hourani.

  Many cancers might be influenced by obesity, including breast cancer, the leading cause of cancer death among women. Obesity is a complex state associated with multiple physiological and molecular changes capable of modulating the behavior of breast tumor cells and the surrounding microenvironment. This review discussed the inverse association between obesity and breast cancer among premenopausal breast cancer females and the positive association among postmenopausal. Four mechanisms may link obesity and breast cancer including leptin and leptin receptor expression, adipose chronic inflammation, sex hormone alternation, and insulin and insulinlike growth factor 1 (IGF-1) signaling. Leptin has been involved in breast cancer initiation, development, and progression through signaling transduction network. Leptin functions are strengthened through cross talk with multiple oncogenes, cytokines, and growth factors. Adipose chronic inflammation promotes cancer growth and angiogenesis and modifies the immune responses. A pro-inflammatory microenvironment at tumor site promotes cytokines and pro-inflammatory mediators adjacent to the tumor. Leptin stimulates pro-inflammatory cytokines and promotes T-helper 1 responses. Obesity is common of chronic inflammation. In obese patients, white adipose tissue (WAT) will promote pro-inflammatory mediators that will encourage tumor growth and WAT inflammation. Sex hormone alternation of estrogens is associated with increased risk for hormone-sensitive breast cancers. Estrogens cause tumorigenesis by its effect on signaling pathways that lead to DNA damage, stimulation angiogenesis, mutagenesis, and cell proliferation. In postmenopausal females, and due to termination of ovarian function, estrogens were produced extra gonadally, mainly in peripheral adipose tissues where adrenal-produced androgen precursors are converted to estrogens. Active estradiol leads to breast cancer development by binding to ERα, which is modified by receptor's interaction of various signal transduction pathways. Hyperinsulinemia and IGF-1 activate the MAPK and PI3K pathways, leading to cancer-promoting effects. Cross talk between insulin/IGF and estrogen signaling pathways promotes hormone-sensitive breast cancer development. Hyperinsulinemia is a risk factor for breast cancer that explains the obesity-breast cancer association. Controlling IGF-1 level and targeting IGF-1 receptors among different breast cancer subtypes may be useful for breast cancer treatment. This review discussed several leptin signaling pathways, highlighting the potential advantage of targeting leptin as a potential target of the novel therapeutic strategies for breast cancer treatment.

Keywords:  Inflammasome; Notch signaling; adipose inflammation; cross talk; insulinlike growth factor 1; leptin; novel therapeutic strategies; obesity

DOI:  https://doi.org/10.1177/1178223419898458
Nature. 2020 Jan 20.

The single-cell pathology landscape of breast cancer.

Hartland W Jackson, Jana R Fischer, Vito R T Zanotelli, H Raza Ali, Robert Mechera, Savas D Soysal, Holger Moch, Simone Muenst, Zsuzsanna Varga, Walter P Weber, Bernd Bodenmiller.

Single-cell analyses have revealed extensive heterogeneity between and within human tumours1-4, but complex single-cell phenotypes and their spatial context are not at present reflected in the histological stratification that is the foundation of many clinical decisions. Here we use imaging mass cytometry5 to simultaneously quantify 35 biomarkers, resulting in 720 high-dimensional pathology images of tumour tissue from 352 patients with breast cancer, with long-term survival data available for 281 patients. Spatially resolved, single-cell analysis identified the phenotypes of tumour and stromal single cells, their organization and their heterogeneity, and enabled the cellular architecture of breast cancer tissue to be characterized on the basis of cellular composition and tissue organization. Our analysis reveals multicellular features of the tumour microenvironment and novel subgroups of breast cancer that are associated with distinct clinical outcomes. Thus, spatially resolved, single-cell analysis can characterize intratumour phenotypic heterogeneity in a disease-relevant manner, with the potential to inform patient-specific diagnosis.

DOI: https://doi.org/10.1038/s41586-019-1876-x
Curr Biol. 2020 Jan 20. pii: S0960-9822(19)31592-1. [Epub ahead of print]30(2): R89-R91

Amino Acid Sensing: Architecture of mTORC1 on the Lysosome Surface.

Wei Peng, Jenna L Jewell.

Amino acid signaling through the Rag GTPases promotes mTORC1 lysosomal localization and subsequent activation. Two new cryo-EM structures examine the architecture of the Rag GTPase heterodimers complexed with mTORC1.

DOI: https://doi.org/10.1016/j.cub.2019.11.087
Curr Opin Cell Biol. 2020 Jan 20. pii: S0955-0674(19)30117-6. [Epub ahead of print]63 57-67

Novel roles of phosphoinositides in signaling, lipid transport, and disease.

Gerald R V Hammond, John E Burke.

  Phosphoinositides (PPIns) are lipid signaling molecules that act as master regulators of cellular signaling. Recent studies have revealed novel roles of PPIns in myriad cellular processes and multiple human diseases mediated by misregulation of PPIn signaling. This review will present a timely summary of recent discoveries in PPIn biology, specifically their role in regulating unexpected signaling pathways, modification of signaling outcomes downstream of integral membrane proteins, and novel roles in lipid transport. This has revealed new roles of PPIns in regulating membrane trafficking, immunity, cell polarity, and response to extracellular signals. A specific focus will be on novel opportunities to target PPIn metabolism for treatment of human diseases, including cancer, pathogen infection, developmental disorders, and immune disorders.

Keywords:  Flippases; GPCR; Ion channels; Lipid kinases; Lipid signaling; Lipid transfer proteins; Membrane contact sites; Membrane trafficking; PI3P; PI4KB; PI4P; PIK3CA; PIP2; PIP3; Phosphatidylinositol; Phosphoinositide kinases; Phosphoinositides

DOI:  https://doi.org/10.1016/j.ceb.2019.12.007
Cancers (Basel). 2020 Jan 21. pii: E259. [Epub ahead of print]12(2):

Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer.

Priya D Gopal Krishnan, Emily Golden, Eleanor A Woodward, Nathan J Pavlos, Pilar Blancafort.

  The Rab GTPase family of proteins are mediators of membrane trafficking, conferring identity to the cell membranes. Recently, Rab and Rab-associated factors have been recognized as major regulators of the intracellular positioning and activity of signaling pathways regulating cell growth, survival and programmed cell death or apoptosis. Membrane trafficking mediated by Rab proteins is controlled by intracellular localization of Rab proteins, Rab-membrane interactions and GTP-activation processes. Aberrant expression of Rab proteins has been reported in multiple cancers such as lung, brain and breast malignancies. Mutations in Rab-coding genes and/or post-translational modifications in their protein products disrupt the cellular vesicle trafficking network modulating tumorigenic potential, cellular migration and metastatic behavior. Conversely, Rabs also act as tumor suppressive factors inducing apoptosis and inhibiting angiogenesis. Deconstructing the signaling mechanisms modulated by Rab proteins during apoptosis could unveil underlying molecular mechanisms that may be exploited therapeutically to selectively target malignant cells.

Keywords:  PI3K-AKT-mTOR; Rab GTPase; apoptosis; cancer

DOI:  https://doi.org/10.3390/cancers12020259
Transl Res. 2019 Dec 27. pii: S1931-5244(19)30257-9. [Epub ahead of print]

Proteomic analysis of malignant and benign endometrium according to obesity and insulin-resistance status using Reverse Phase Protein Array.

Olivia Raglan, Nada Assi, Jaya Nautiyal, Haonan Lu, Hani Gabra, Marc J Gunter, Maria Kyrgiou.

Obesity and hyperinsulinemia are known risk factors for endometrial cancer, yet the biological pathways underlying this relationship are incompletely understood. This study investigated protein expression in endometrial cancer and benign tissue and its correlation with obesity and insulin resistance. One hundred and seven women undergoing hysterectomy for endometrial cancer or benign conditions provided a fasting blood sample and endometrial tissue. We performed proteomic expression according to body mass index, insulin resistance, and serum marker levels. We used linear regression and independent t test for statistical analysis. Proteomic data from 560 endometrial cancer cases from The Cancer Genome Atlas (TCGA) databank were used to assess reproducibility of results. One hundred and twenty seven proteins were significantly differentially expressed between 66 cancer and 26 benign patients. Protein expression involved in cell cycle progression, impacting cytoskeletal dynamics (PAK1) and cell survival (Rab 25), were most significantly altered. Obese women with cancer had increased PRAS40_pT246; a downstream marker of increased PI3K-AKT signaling. Obese women without cancer had increased mitogenic and antiapoptotic signaling by way of upregulation of Mcl-1, DUSP4, and Insulin Receptor-b. This exploratory study identified a number of candidate proteins specific to endometrioid endometrial cancer and benign endometrial tissues. Obesity and insulin resistance in women with benign endometrium leads to specific upregulation of proteins involved in insulin and driver oncogenic signaling pathways such as the PI3K-AKT-mTOR and growth factor signaling pathways which are mitogenic and also disruptive to metabolism.

DOI: https://doi.org/10.1016/j.trsl.2019.12.003
Trends Biochem Sci. 2020 Jan 16. pii: S0968-0004(19)30263-4. [Epub ahead of print]

Stable Isotopes for Tracing Mammalian-Cell Metabolism In Vivo.

Juan Fernández-García, Patricia Altea-Manzano, Erica Pranzini, Sarah-Maria Fendt.

  Metabolism is at the cornerstone of all cellular functions and mounting evidence of its deregulation in different diseases emphasizes the importance of a comprehensive understanding of metabolic regulation at the whole-organism level. Stable-isotope measurements are a powerful tool for probing cellular metabolism and, as a result, are increasingly used to study metabolism in in vivo settings. The additional complexity of in vivo metabolic measurements requires paying special attention to experimental design and data interpretation. Here, we review recent work where in vivo stable-isotope measurements have been used to address relevant biological questions within an in vivo context, summarize different experimental and data interpretation approaches and their limitations, and discuss future opportunities in the field.

Keywords:  in vivo metabolism; metabolic models; stable-isotope tracers; tracer analysis

DOI:  https://doi.org/10.1016/j.tibs.2019.12.002
Nat Commun. 2020 Jan 23. 11(1): 465

Chaperone mediated detection of small molecule target binding in cells.

Kelvin F Cho, Taylur P Ma, Christopher M Rose, Donald S Kirkpatrick, Kebing Yu, Robert A Blake.

The ability to quantitatively measure a small molecule's interactions with its protein target(s) is crucial for both mechanistic studies of signaling pathways and in drug discovery. However, current methods to achieve this have specific requirements that can limit their application or interpretation. Here we describe a complementary target-engagement method, HIPStA (Heat Shock Protein Inhibition Protein Stability Assay), a high-throughput method to assess small molecule binding to endogenous, unmodified target protein(s) in cells. The methodology relies on the change in protein turnover when chaperones, such as HSP90, are inhibited and the stabilization effect that drug-target binding has on this change. We use HIPStA to measure drug binding to three different classes of drug targets (receptor tyrosine kinases, nuclear hormone receptors, and cytoplasmic protein kinases), via quantitative fluorescence imaging. We further demonstrate its utility by pairing the method with quantitative mass spectrometry to identify previously unknown targets of a receptor tyrosine kinase inhibitor.

DOI: https://doi.org/10.1038/s41467-019-14033-0
Mol Cell. 2020 Jan 08. pii: S1097-2765(19)30952-9. [Epub ahead of print]

A Cancer-Specific Ubiquitin Ligase Drives mRNA Alternative Polyadenylation by Ubiquitinating the mRNA 3' End Processing Complex.

Seung Wook Yang, Lei Li, Jon P Connelly, Shaina N Porter, Kiran Kodali, Haiyun Gan, Jung Mi Park, Klementina Fon Tacer, Heather Tillman, Junmin Peng, Shondra M Pruett-Miller, Wei Li, Patrick Ryan Potts.

  Alternative polyadenylation (APA) contributes to transcriptome complexity by generating mRNA isoforms with varying 3' UTR lengths. APA leading to 3' UTR shortening (3' US) is a common feature of most cancer cells; however, the molecular mechanisms are not understood. Here, we describe a widespread mechanism promoting 3' US in cancer through ubiquitination of the mRNA 3' end processing complex protein, PCF11, by the cancer-specific MAGE-A11-HUWE1 ubiquitin ligase. MAGE-A11 is normally expressed only in the male germline but is frequently re-activated in cancers. MAGE-A11 is necessary for cancer cell viability and is sufficient to drive tumorigenesis. Screening for targets of MAGE-A11 revealed that it ubiquitinates PCF11, resulting in loss of CFIm25 from the mRNA 3' end processing complex. This leads to APA of many transcripts affecting core oncogenic and tumor suppressors, including cyclin D2 and PTEN. These findings provide insights into the molecular mechanisms driving APA in cancer and suggest therapeutic strategies.

Keywords:  3′ UTR shortening; 3′ end processing complex; CFIm25; HUWE1; MAGE-A11; PCF11; PTEN; alternative polyadenylation; cyclin D2; ubiquitin

DOI:  https://doi.org/10.1016/j.molcel.2019.12.022
APMIS. 2020 Jan 24.

Hierarchical clustering of PI3K and MAPK pathway proteins in breast cancer intrinsic subtypes.

Dinja T Kruger, Mark Opdam, Joyce Sanders, Vincent van der Noort, Epie Boven, Sabine C Linn.

  The phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase(MAPK) pathways are frequently activated in breast cancer. We recently demonstrated the importance of analyzing multiple proteins as read-out for pathway activation in ER+/HER2- breast cancer, since single proteins are known to provide insufficient information. Here, we determined pathway activation in other primary breast cancer intrinsic subtypes derived from postmenopausal patients. Tumor blocks were recollected and immunohistochemistry was performed using antibodies against PTEN, p-AKT(Thr308), p-AKT(Ser473), p-p70S6K, p-4EBP1, p-S6RP(Ser235/236) and p-ERK1/2, followed by unsupervised hierarchical clustering. In 32 ER+/HER2+, 37 ER-/HER2+ and 74 triple-negative breast cancer patients, subgroups were identified with preferentially activated (A) and preferentially not activated (N) proteins. These subgroups likely reflect tumors with differences in biological behavior as well as treatment outcome.

Keywords:  HER2-positive breast cancer; breast cancer intrinsic subtypes; hierarchical clustering; mitogen-activated protein kinase; phosphatidylinositol-3-kinase; triple-negative breast cancer

DOI:  https://doi.org/10.1111/apm.13026
Elife. 2020 Jan 21. pii: e50342. [Epub ahead of print]9

Receptor-based mechanism of relative sensing and cell memory in mammalian signaling networks.

Eugenia Lyashenko, Mario Niepel, Purushottam D Dixit, Sang Kyun Lim, Peter K Sorger, Dennis Vitkup.

  Detecting relative rather than absolute changes in extracellular signals enables cells to make decisions in fluctuating environments. However, how mammalian signaling networks store the memories of past stimuli and subsequently use them to compute relative signals, i.e. perform fold change detection, is not well understood. Using the growth factor-activated PI3K-Akt signaling pathway, we develop computational and analytical models, and experimentally validate a novel mechanism of relative sensing in mammalian cells. This mechanism relies on a new form of cellular memory, where cells effectively encode past stimulation levels in the abundance of cognate receptors on the cell surface. We show the robustness and specificity of the relative sensing for two physiologically important ligands, epidermal growth factor (EGF) and hepatocyte growth factor (HGF), and across wide ranges of background stimuli. Our results suggest that similar mechanisms of memory and fold change detection are likely to be important across diverse signaling cascades and biological contexts.

Keywords:  computational biology; human; physics of living systems; systems biology

DOI:  https://doi.org/10.7554/eLife.50342
J Med Chem. 2020 Jan 19.

Discovery of a Brain Penetrant ATP-competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS disorders.

Simone Bonazzi, Carleton P Goold, Audrey Gray, Noel M Thomsen, Jill Nunez, Rajeshri Karki, Aakruti Gorde, Jonathan D Biag, Hasnain A Malik, Yingchuan Sun, Guiqing Liang, Danuta Lubicka, Sarah Salas, Nancy Labbe-Giguere, Erin P Keaney, Stephanie McTighe, Shanming Liu, Lin Deng, Grazia Piizzi, Franco Lombardo, Doug Burdette, Jean-Cosme Dodart, Christopher John Wilson, Stefan Peukert, Daniel Curtis, Lawrence G Hamann, Leon O Murphy.

Recent clinical evaluation of Everolimus for seizure reduction in patients with Tuberous Sclerosis Complex (TSC), a disease with overactivated mTOR signaling, has demonstrated the therapeutic value of mTOR inhibitors for Central Nervous System (CNS) indications. Given that Everolimus is an incomplete inhibitor of mTOR function we sought to develop a new mTOR inhibitor that has improved properties and is suitable for CNS disorders. Starting from an in-house purine-based compound, optimization of the physicochemical properties of a thiazolopyrimidine series led to the discovery of the small molecule 7, a potent and selective brain penetrant ATP-competitive mTOR inhibitor. In neuronal cell-based models of mTOR hyperactivity, 7 corrected mTOR pathway activity and the resulting neuronal overgrowth phenotype. The new mTOR inhibitor 7 showed good brain exposure and significantly improved the survival rate of mice with neuronal-specific ablation of the Tsc1 gene. These results demonstrate the potential utility of this tool compound to test therapeutic hypotheses that depend on mTOR hyperactivity in the CNS.

DOI: https://doi.org/10.1021/acs.jmedchem.9b01398
BMJ Open Diabetes Res Care. 2020 01;pii: e000801. [Epub ahead of print]8(1):

Medication-induced hyperglycemia: pediatric perspective.

Mustafa Tosur, Johanna Viau-Colindres, Marcela Astudillo, Maria Jose Redondo, Sarah K Lyons.

  Medication-induced hyperglycemia is a frequently encountered clinical problem in children. The intent of this review of medications that cause hyperglycemia and their mechanisms of action is to help guide clinicians in prevention, screening and management of pediatric drug-induced hyperglycemia. We conducted a thorough literature review in PubMed and Cochrane libraries from inception to July 2019. Although many pharmacotherapies that have been associated with hyperglycemia in adults are also used in children, pediatric-specific data on medication-induced hyperglycemia are scarce. The mechanisms of hyperglycemia may involve β cell destruction, decreased insulin secretion and/or sensitivity, and excessive glucose influx. While some medications (eg, glucocorticoids, L-asparaginase, tacrolimus) are markedly associated with high risk of hyperglycemia, the association is less clear in others (eg, clonidine, hormonal contraceptives, amiodarone). In addition to the drug and its dose, patient characteristics, such as obesity or family history of diabetes, affect a child's risk of developing hyperglycemia. Identification of pediatric patients with increased risk of developing hyperglycemia, creating strategies for risk reduction, and treating hyperglycemia in a timely manner may improve patient outcomes.

Keywords:  hyperglycemia; medications; pancreatic diabetes; pediatrics

DOI:  https://doi.org/10.1136/bmjdrc-2019-000801
Nat Commun. 2020 Jan 23. 11(1): 454

TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells.

Cyril Corbet, Estelle Bastien, Joao Pedro Santiago de Jesus, Emeline Dierge, Ruben Martherus, Catherine Vander Linden, Bastien Doix, Charline Degavre, Céline Guilbaud, Laurenne Petit, Carine Michiels, Chantal Dessy, Yvan Larondelle, Olivier Feron.

Acidosis, a common characteristic of the tumor microenvironment, is associated with alterations in metabolic preferences of cancer cells and progression of the disease. Here we identify the TGF-β2 isoform at the interface between these observations. We document that acidic pH promotes autocrine TGF-β2 signaling, which in turn favors the formation of lipid droplets (LD) that represent energy stores readily available to support anoikis resistance and cancer cell invasiveness. We find that, in cancer cells of various origins, acidosis-induced TGF-β2 activation promotes both partial epithelial-to-mesenchymal transition (EMT) and fatty acid metabolism, the latter supporting Smad2 acetylation. We show that upon TGF-β2 stimulation, PKC-zeta-mediated translocation of CD36 facilitates the uptake of fatty acids that are either stored as triglycerides in LD through DGAT1 or oxidized to generate ATP to fulfill immediate cellular needs. We also address how, by preventing fatty acid mobilization from LD, distant metastatic spreading may be inhibited.

DOI: https://doi.org/10.1038/s41467-019-14262-3
J Nutr. 2020 Jan 21. pii: nxz301. [Epub ahead of print]

Regulation of mTORC1 by Small GTPases in Response to Nutrients.

Min Zhu, Xiu-Qi Wang.

  Mechanistic target of rapamycin complex 1 (mTORC1) is a highly evolutionarily conserved serine/threonine kinase that regulates cell growth and metabolism in response to multiple environmental cues, such as nutrients, hormones, energy, and stress. Deregulation of mTORC1 can lead to diseases such as diabetes, obesity, and cancer. A series of small GTPases, including Rag, Ras homolog enriched in brain (Rheb), adenosine diphosphate ribosylation factor 1 (Arf1), Ras-related protein Ral-A, Ras homolog (Rho), and Rab, are involved in regulating mTORC1 in response to nutrients, and mTORC1 is differentially regulated via these small GTPases according to specific conditions. Leucine and arginine sensing are considered to be well-confirmed amino acid-sensing signals, activating mTORC1 via a Rag GTPase-dependent mechanism as well as the Ragulator complex and vacuolar H+-adenosine triphosphatase (v-ATPase). Glutamine promotes mTORC1 activation via Arf1 independently of the Rag GTPase. In this review, we summarize current knowledge regarding the regulation of mTORC1 activity by small GTPases in response to nutrients, focusing on the function of small GTPases in mTORC1 activation and how small GTPases are regulated by nutrients.

Keywords:  arginine; glutamine; leucine; mTORC1; small GTPases

DOI:  https://doi.org/10.1093/jn/nxz301
Nat Commun. 2020 Jan 24. 11(1): 481

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype.

Agian Jeffilano Barinda, Koji Ikeda, Dhite Bayu Nugroho, Donytra Arby Wardhana, Naoto Sasaki, Sakiko Honda, Ryota Urata, Satoaki Matoba, Ken-Ichi Hirata, Noriaki Emoto.

Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.

DOI: https://doi.org/10.1038/s41467-020-14387-w