bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2020–07–26
nineteen papers selected by
Ralitsa Radostinova Madsen, University College London
  1. Hepatic Peroxisomal β-Oxidation Suppresses Lipophagy via RPTOR Acetylation and MTOR Activation.
  2. Testing considerations for phosphatidylinositol-3-kinase catalytic subunit alpha as an emerging biomarker in advanced breast cancer.
  3. Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity.
  4. Progesterone receptor membrane component 1 promotes the growth of breast cancers by altering the phosphoproteome and augmenting EGFR/PI3K/AKT signalling.
  5. The Tumor Suppressor PTEN as Molecular Switch Node Regulating Cell Metabolism and Autophagy: Implications in Immune System and Tumor Microenvironment.
  6. PIK3CA Mutations and Their Impact on Survival Outcomes of Patients with Cervical Cancer: A Systematic Review.
  7. Insulin signaling and glucose metabolism in different hepatoma cell lines deviate from hepatocyte physiology toward a convergent aberrant phenotype.
  8. Chemical strategies to overcome resistance against targeted anticancer therapeutics.
  9. Non-invasive early detection of cancer four years before conventional diagnosis using a blood test.
  10. Nutrients men-TOR β-Cells to Adulthood.
  11. N-myristoyltransferase-1 is necessary for lysosomal degradation and mTORC1 activation in cancer cells.
  12. Tracking cells in epithelial acini by light sheet microscopy reveals proximity effects in breast cancer initiation.
  13. PIK3CA vascular overgrowth syndromes: an update.
  14. Epigenomic State Transitions Characterize Tumor Progression in Mouse Lung Adenocarcinoma.
  15. Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells.
  16. Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.
  17. The activities of drug inactive ingredients on biological targets.
  18. Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.
  19. Proteome activity landscapes of tumor cell lines determine drug responses.
  1. Autophagy. 2020 Jul 20.
    Hepatic Peroxisomal β-Oxidation Suppresses Lipophagy via RPTOR Acetylation and MTOR Activation.
    Anyuan He, John M Dean, Dongliang Lu, Yali Chen, Irfan J Lodhi.
      Hepatic lipid homeostasis is controlled by a coordinated regulation of various metabolic pathways involved in de novo synthesis, uptake, storage, and catabolism of lipids. Disruption of this balance could lead to hepatic steatosis. Peroxisomes play an essential role in lipid metabolism, yet their importance is often overlooked. In a recent study, we demonstrated a role for hepatic peroxisomal β-oxidation in autophagic degradation of lipid droplets. ACOX1 (acyl-Coenzyme A oxidase 1, palmitoyl), the rate-limiting enzyme of peroxisomal β-oxidation, increases with fasting or high-fat diet (HFD). Liver-specific acox1 knockout (acox1-LKO) protects mice from hepatic steatosis induced by starvation or HFD via induction of lipophagy. Mechanistically, we showed that hepatic ACOX1 deficiency decreases the total cytosolic acetyl-CoA levels, which leads to reduced acetylation of RPTOR/RAPTOR, a component of MTORC1, which is a key regulator of macroautophagy/autophagy. These results identify peroxisome-derived acetyl-CoA as a critical metabolic regulator of autophagy that controls hepatic lipid homeostasis.
    Keywords:  ACOX1; MTORC1; NAFLD; autophagy; lipids; lipophagy; lysosome; peroxisome
    DOI:  https://doi.org/10.1080/15548627.2020.1797288
  2. Cancer Med. 2020 Jul 22.
    Testing considerations for phosphatidylinositol-3-kinase catalytic subunit alpha as an emerging biomarker in advanced breast cancer.
    Deborah L Toppmeyer, Michael F Press.
      Breast cancer is the most common cancer in women, and approximately 71% of carcinomas are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-not-amplified (HER2-negative). Pathogenesis of breast cancer is associated with dysregulation of several signaling pathways, including the phosphatidylinositol-3-kinase (PI3K) pathway. PIK3CA, the gene encoding PI3K catalytic subunit p110α, is mutated in 20%-40% of breast cancer patients. Several PI3K inhibitors have been developed and one, alpelisib, was recently approved for use in PIK3CA-mutated, HR+, HER2-negative advanced breast cancer. There are numerous types of assays and methods used in clinical studies to determine PIK3CA status in cancers. Additionally, there are several factors to consider for PIK3CA testing in clinical practice, including choice of assay, source of sample, and test timing. In this review, we discuss the use of PIK3CA as a biomarker to guide treatment decisions in patients with HR+, HER2-negative advanced breast cancer, as well as practical considerations and recommendations for testing.
    Keywords:   PIK3CA ; advanced breast cancer; alpelisib; biomarker; companion diagnostic
    DOI:  https://doi.org/10.1002/cam4.3278
  3. Nat Metab. 2019 Jan;1(1): 133-146
    Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity.
    Pauline Morigny, Marianne Houssier, Aline Mairal, Claire Ghilain, Etienne Mouisel, Fadila Benhamed, Bernard Masri, Emeline Recazens, Pierre-Damien Denechaud, Geneviève Tavernier, Sylvie Caspar-Bauguil, Sam Virtue, Veronika Sramkova, Laurent Monbrun, Anne Mazars, Madjid Zanoun, Sandra Guilmeau, Valentin Barquissau, Diane Beuzelin, Sophie Bonnel, Marie Marques, Boris Monge-Roffarello, Corinne Lefort, Barbara Fielding, Thierry Sulpice, Arne Astrup, Bernard Payrastre, Justine Bertrand-Michel, Emmanuelle Meugnier, Laetitia Ligat, Frédéric Lopez, Hervé Guillou, Charlotte Ling, Cecilia Holm, Remi Rabasa-Lhoret, Wim H M Saris, Vladimir Stich, Peter Arner, Mikael Rydén, Cedric Moro, Nathalie Viguerie, Matthew Harms, Stefan Hallén, Antonio Vidal-Puig, Hubert Vidal, Catherine Postic, Dominique Langin.
      Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.
    Keywords:  ChREBP; ELOVL Fatty Acid Elongase 6; ELOVL6 Expression; Hormone-sensitive Lipase; Insulin Signaling
    DOI:  https://doi.org/10.1038/s42255-018-0007-6
  4. Br J Cancer. 2020 Jul 24.
    Progesterone receptor membrane component 1 promotes the growth of breast cancers by altering the phosphoproteome and augmenting EGFR/PI3K/AKT signalling.
    Diego A Pedroza, Venkatesh Rajamanickam, Ramadevi Subramani, Alejandra Bencomo, Adriana Galvez, Rajkumar Lakshmanaswamy.
       BACKGROUND: Increased expression of the progesterone receptor membrane component 1 (PGRMC1) has been linked to multiple cancers, including breast cancer. Despite being a regulatory receptor and a potential therapeutic target, the oncogenic potential of PGRMC1 has not been studied.
    METHODS: The impact of PGRMC1 on breast cancer growth and progression was studied following chemical inhibition and alteration of PGRMC1 expression, and evaluated by using online-based gene expression datasets of human breast cancer tissue. MTS, flow cytometry, qPCR, Western blotting, confocal microscopy and phosphoproteome analysis were performed.
    RESULTS: We observed higher PGRMC1 levels in both ER-positive ZR-75-1 and TNBC MDA-MB-468 cells. Both chemical inhibition and silencing decreased cell proliferation, induced cell-cycle arrest, promoted apoptosis and reduced the migratory and invasive capabilities of ZR-75-1 and MDA-MB-468 cells. Further, phosphoproteome analysis demonstrated an overall decrease in activation of proteins involved in PI3K/AKT/mTOR and EGFR signalling pathways. In contrast, overexpression of PGRMC1 in non-malignant MCF10A cells resulted in increased cell proliferation, and enhanced activity of PI3K/AKT/mTOR and EGFR signalling pathways.
    CONCLUSIONS: Our data demonstrate that PGRMC1 plays a prominent role in regulating the growth of cancer cells by altering the PI3K/AKT/mTOR and EGFR signalling mechanisms in both ER-positive and TNBC cells.
    DOI:  https://doi.org/10.1038/s41416-020-0992-6
  5. Cells. 2020 Jul 18. pii: E1725. [Epub ahead of print]9(7):
    The Tumor Suppressor PTEN as Molecular Switch Node Regulating Cell Metabolism and Autophagy: Implications in Immune System and Tumor Microenvironment.
    Saveria Aquila, Marta Santoro, Annalisa Caputo, Maria Luisa Panno, Vincenzo Pezzi, Francesca De Amicis.
      Recent studies conducted over the past 10 years evidence the intriguing role of the tumor suppressor gene Phosphatase and Tensin Homolog deleted on Chromosome 10 PTEN in the regulation of cellular energy expenditure, together with its capability to modulate proliferation and survival, thus expanding our knowledge of its physiological functions. Transgenic PTEN mice models are resistant to oncogenic transformation, present decreased adiposity and reduced cellular glucose and glutamine uptake, together with increased mitochondrial oxidative phosphorylation. These acquisitions led to a novel understanding regarding the role of PTEN to counteract cancer cell metabolic reprogramming. Particularly, PTEN drives an "anti-Warburg state" in which less glucose is taken up, but it is more efficiently directed to the mitochondrial Krebs cycle. The maintenance of cellular homeostasis together with reduction of metabolic stress are controlled by specific pathways among which autophagy, a catabolic process strictly governed by mTOR and PTEN. Besides, a role of PTEN in metabolic reprogramming and tumor/stroma interactions in cancer models, has recently been established. The genetic inactivation of PTEN in stromal fibroblasts of mouse mammary glands, accelerates breast cancer initiation and progression. This review will discuss our novel understanding in the molecular connection between cell metabolism and autophagy by PTEN, highlighting novel implications regarding tumor/stroma/immune system interplay. The newly discovered action of PTEN opens innovative avenues for investigations relevant to counteract cancer development and progression.
    Keywords:  Warburg state; cancer metabolism; immune system; stroma
    DOI:  https://doi.org/10.3390/cells9071725
  6. Acta Cytol. 2020 Jul 17. 1-9
    PIK3CA Mutations and Their Impact on Survival Outcomes of Patients with Cervical Cancer: A Systematic Review.
    Vasilios Pergialiotis, Christina Nikolaou, Dimitrios Haidopoulos, Maximos Frountzas, Nikolaos Thomakos, Ioannis Bellos, Angeliki Papapanagiotou, Alexandros Rodolakis.
       INTRODUCTION: Several studies have implicated the PIK3/AKT pathway in the pathophysiology of cancer progression as its activation seems to be aberrant in several forms of cancer. The purpose of the present systematic review is to evaluate the impact of PIK3CA mutations on survival outcomes of patients with cervical cancer.
    METHODS: We used the Medline (1966-2020), Scopus (2004-2020), ClinicalTrials.gov (2008-2020), EMBASE (1980-2020), Cochrane Central Register of Controlled Trials (CENTRAL) (1999-2020), and Google Scholar (2004-2020) databases in our primary search along with the reference lists of electronically retrieved full-text papers. Statistical meta-analysis was performed with the RevMan 5.3 software.
    RESULTS: Overall, 12 articles were included in the present study that comprised 2,196 women with cervical cancer. Of those, 3 studies did not report significant differences in survival outcomes among patients with mutated versus wild-type PIK3CA tumors, 5 studies reported decreased survival outcomes, and 3 studies revealed increased survival rates. The meta-analysis revealed that patients with the mutated PIK3CA genotypes had worse overall survival compared to patients with wild-type PIK3CA (HR 2.31; 95% CI: 1.51, 3.55; 95% PI: 0.54, 9.96; data from 3 studies) and the same was observed in the case of DFS rates (HR 1.82; 95% CI: 1.47, 2.25; 95% PI: 1.29, 2.56; data from 4 studies).
    CONCLUSION: Current evidence concerning the impact of PIK3CA mutations on survival outcomes of patients with cervical cancer is inconclusive, although the majority of included studies support a potential negative effect, primarily among those with squamous cell carcinoma tumors.
    Keywords:  Cervical cancer; Meta-analysis; PI3K; PIK3; Survival; Systematic review
    DOI:  https://doi.org/10.1159/000509095
  7. Sci Rep. 2020 Jul 21. 10(1): 12031
    Insulin signaling and glucose metabolism in different hepatoma cell lines deviate from hepatocyte physiology toward a convergent aberrant phenotype.
    Angela Molinaro, Barbara Becattini, Giovanni Solinas.
      Hepatoma cell lines are widely used to model the hepatocyte for insulin signaling and fatty liver disease. However, a direct comparison of insulin action in primary hepatocytes and in hepatoma cell lines is needed to validate this model and to better understand liver cancer. Here we have investigated insulin signaling, gluconeogenic gene expression, glucose production, and fatty acid synthase abundance in primary hepatocytes and in HepG2, Hepa 1-6, and McARH7777 hepatoma cell lines. Differences in the electrophoretic profiles of protein extracts from human and mouse primary hepatocytes and the hepatoma cells lines are shown. Compared to primary hepatocytes, hepatoma cells showed high basal phosphorylation of AKT at Thr 308 and constitutively activated RAS-MAPK signaling, which were resistant to the dominant negative Ras mutant H-Ras17N. Hepatoma cell lines also showed defective expression of gluconeogenic enzymes, insulin unresponsive GSK phosphorylation, and marginal glucose production. Hepatoma cells also showed lower protein levels of fatty acid synthase and a largely distinct protein electrophoresis profile from hepatocytes but similar between different hepatoma lines. We conclude that hepatoma cell lines do not accurately model the hepatocyte for insulin action but may be valuable tools to investigate the proteomic changes conferring to hepatocellular carcinoma its peculiar metabolisms.
    DOI:  https://doi.org/10.1038/s41598-020-68721-9
  8. Nat Chem Biol. 2020 Aug;16(8): 817-825
    Chemical strategies to overcome resistance against targeted anticancer therapeutics.
    Rudolf Pisa, Tarun M Kapoor.
      Emergence of resistance is a major factor limiting the efficacy of molecularly targeted anticancer drugs. Understanding the specific mutations, or other genetic or cellular changes, that confer drug resistance can help in the development of therapeutic strategies with improved efficacies. Here, we outline recent progress in understanding chemotype-specific mechanisms of resistance and present chemical strategies, such as designing drugs with distinct binding modes or using proteolysis targeting chimeras, to overcome resistance. We also discuss how targeting multiple binding sites with bifunctional inhibitors or identifying collateral sensitivity profiles can be exploited to limit the emergence of resistance. Finally, we highlight how incorporating analyses of resistance early in drug development can help with the design and evaluation of therapeutics that can have long-term benefits for patients.
    DOI:  https://doi.org/10.1038/s41589-020-0596-8
  9. Nat Commun. 2020 Jul 21. 11(1): 3475
    Non-invasive early detection of cancer four years before conventional diagnosis using a blood test.
    Xingdong Chen, Jeffrey Gole, Athurva Gore, Qiye He, Ming Lu, Jun Min, Ziyu Yuan, Xiaorong Yang, Yanfeng Jiang, Tiejun Zhang, Chen Suo, Xiaojie Li, Lei Cheng, Zhenhua Zhang, Hongyu Niu, Zhe Li, Zhen Xie, Han Shi, Xiang Zhang, Min Fan, Xiaofeng Wang, Yajun Yang, Justin Dang, Catie McConnell, Juan Zhang, Jiucun Wang, Shunzhang Yu, Weimin Ye, Yuan Gao, Kun Zhang, Rui Liu, Li Jin.
      Early detection has the potential to reduce cancer mortality, but an effective screening test must demonstrate asymptomatic cancer detection years before conventional diagnosis in a longitudinal study. In the Taizhou Longitudinal Study (TZL), 123,115 healthy subjects provided plasma samples for long-term storage and were then monitored for cancer occurrence. Here we report the preliminary results of PanSeer, a noninvasive blood test based on circulating tumor DNA methylation, on TZL plasma samples from 605 asymptomatic individuals, 191 of whom were later diagnosed with stomach, esophageal, colorectal, lung or liver cancer within four years of blood draw. We also assay plasma samples from an additional 223 cancer patients, plus 200 primary tumor and normal tissues. We show that PanSeer detects five common types of cancer in 88% (95% CI: 80-93%) of post-diagnosis patients with a specificity of 96% (95% CI: 93-98%), We also demonstrate that PanSeer detects cancer in 95% (95% CI: 89-98%) of asymptomatic individuals who were later diagnosed, though future longitudinal studies are required to confirm this result. These results demonstrate that cancer can be non-invasively detected up to four years before current standard of care.
    DOI:  https://doi.org/10.1038/s41467-020-17316-z
  10. Dev Cell. 2020 Jul 20. pii: S1534-5807(20)30507-4. [Epub ahead of print]54(2): 140-141
    Nutrients men-TOR β-Cells to Adulthood.
    Keiichi Katsumoto, Anne Grapin-Botton.
      A major trigger of adult β-cell insulin secretion is glucose. In a recent issue of Cell Metabolism, Helman and colleagues show that in fetuses insulin secretion depends on the activation of mTOR by amino acids and that reducing amino acids promotes maturation of β-cells derived from pluripotent stem cells.
    DOI:  https://doi.org/10.1016/j.devcel.2020.06.028
  11. Sci Rep. 2020 Jul 20. 10(1): 11952
    N-myristoyltransferase-1 is necessary for lysosomal degradation and mTORC1 activation in cancer cells.
    Yu-Chuan Chen, Marian S Navarrete, Ying Wang, Natalie C McClintock, Reiko Sakurai, Feng Wang, Kathryn T Chen, Tsui-Fen Chou, Virender K Rehan, Delphine J Lee, Begoña Diaz.
      N-myristoyltransferase-1 (NMT1) catalyzes protein myristoylation, a lipid modification that is elevated in cancer cells. NMT1 sustains proliferation and/or survival of cancer cells through mechanisms that are not completely understood. We used genetic and pharmacological inhibition of NMT1 to further dissect the role of this enzyme in cancer, and found an unexpected essential role for NMT1 at promoting lysosomal metabolic functions. Lysosomes mediate enzymatic degradation of vesicle cargo, and also serve as functional platforms for mTORC1 activation. We show that NMT1 is required for both lysosomal functions in cancer cells. Inhibition of NMT1 impaired lysosomal degradation leading to autophagy flux blockade, and simultaneously caused the dissociation of mTOR from the surface of lysosomes leading to decreased mTORC1 activation. The regulation of lysosomal metabolic functions by NMT1 was largely mediated through the lysosomal adaptor LAMTOR1. Accordingly, genetic targeting of LAMTOR1 recapitulated most of the lysosomal defects of targeting NMT1, including defective lysosomal degradation. Pharmacological inhibition of NMT1 reduced tumor growth, and tumors from treated animals had increased apoptosis and displayed markers of lysosomal dysfunction. Our findings suggest that compounds targeting NMT1 may have therapeutic benefit in cancer by preventing mTORC1 activation and simultaneously blocking lysosomal degradation, leading to cancer cell death.
    DOI:  https://doi.org/10.1038/s41598-020-68615-w
  12. Elife. 2020 Jul 21. pii: e54066. [Epub ahead of print]9
    Tracking cells in epithelial acini by light sheet microscopy reveals proximity effects in breast cancer initiation.
    Ashna Alladin, Lucas Chaible, Lucia Garcia Del Valle, Reither Sabine, Monika Loeschinger, Malte Wachsmuth, Jean-Karim Hériché, Christian Tischer, Martin Jechlinger.
      Cancer clone evolution takes place within tissue ecosystem habitats. But, how exactly tumors arise from a few malignant cells within an intact epithelium is a central, yet unanswered question. This is mainly due to the inaccessibility of this process to longitudinal imaging together with a lack of systems that model the progression of a fraction of transformed cells within a tissue. Here, we developed a new methodology based on primary mouse mammary epithelial acini, where oncogenes can be switched on in single cells within an otherwise normal epithelial cell layer. We combine this stochastic breast tumor induction model with inverted light-sheet imaging to study single-cell behavior for up to four days and analyze cell fates utilizing a newly developed image-data analysis workflow. The power of this integrated approach is illustrated by us finding that small local clusters of transformed cells form tumors while isolated transformed cells do not.
    Keywords:  cancer biology; cell biology; interaction requirements for tumor initiation; light sheet imaging technology; mouse; organoid technology of primary mammary epithelium; scalable big image data analysis pipeline; tractable tumor induction system
    DOI:  https://doi.org/10.7554/eLife.54066
  13. Curr Opin Pediatr. 2020 Aug;32(4): 539-546
    PIK3CA vascular overgrowth syndromes: an update.
    Meagan Hughes, Michelle Hao, Minnelly Luu.
       PURPOSE OF REVIEW: Over the past decade many previously poorly understood vascular malformation disorders have been linked to somatic activating mutations in PIK3CA, which regulates cell survival and growth via activation of the mTOR1-AKT pathway. The goal of this article is to describe and provide an update on the clinical features, complications, and management strategies for the PIK3CA-related overgrowth spectrum (PROS).
    RECENT FINDINGS: PROS encompasses a heterogenous group of disorders with complications related to the tissues harboring the mutation. Vascular malformation syndromes, such as Klippel-Trenaunay syndrome and Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities, have an increased risk of thromboembolic complications, which is accentuated postprocedurally. Asymmetric overgrowth, particularly of limbs, results in a high rate of orthopedic complications. Hypoglycemia screening in the neonatal period and ongoing monitoring for growth failure is recommended in megalencephaly capillary malformation due to its association with multiple endocrinopathies. Recently, sirolimus, an mTOR1 inhibitor, has shown promise in vascular anomalies and now PROS. PIK3CA direct inhibitor, Alpelisib (BYL719), was recently trialed with significant clinical benefit.
    SUMMARY: As the pathogenesis of these conditions is better elucidated and targeted treatments are developed, recognizing the clinical features, comorbidities, and evolving therapeutic landscape across the PROS spectrum becomes more crucial for optimization of care.
    DOI:  https://doi.org/10.1097/MOP.0000000000000923
  14. Cancer Cell. 2020 Jul 07. pii: S1535-6108(20)30310-X. [Epub ahead of print]
    Epigenomic State Transitions Characterize Tumor Progression in Mouse Lung Adenocarcinoma.
    Lindsay M LaFave, Vinay K Kartha, Sai Ma, Kevin Meli, Isabella Del Priore, Caleb Lareau, Santiago Naranjo, Peter M K Westcott, Fabiana M Duarte, Venkat Sankar, Zachary Chiang, Alison Brack, Travis Law, Haley Hauck, Annalisa Okimoto, Aviv Regev, Jason D Buenrostro, Tyler Jacks.
      Regulatory networks that maintain functional, differentiated cell states are often dysregulated in tumor development. Here, we use single-cell epigenomics to profile chromatin state transitions in a mouse model of lung adenocarcinoma (LUAD). We identify an epigenomic continuum representing loss of cellular identity and progression toward a metastatic state. We define co-accessible regulatory programs and infer key activating and repressive chromatin regulators of these cell states. Among these co-accessibility programs, we identify a pre-metastatic transition, characterized by activation of RUNX transcription factors, which mediates extracellular matrix remodeling to promote metastasis and is predictive of survival across human LUAD patients. Together, these results demonstrate the power of single-cell epigenomics to identify regulatory programs to uncover mechanisms and key biomarkers of tumor progression.
    Keywords:  cancer; epigenomics; epithelial-to-mesenchymal transition; metastasis; non-small cell lung cancer; single cell
    DOI:  https://doi.org/10.1016/j.ccell.2020.06.006
  15. Science. 2020 Jul 24. 369(6502): 397-403
    Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells.
    Yi Xu, Yang Zhang, Juan C García-Cañaveras, Lili Guo, Mengyuan Kan, Sixiang Yu, Ian A Blair, Joshua D Rabinowitz, Xiaolu Yang.
      Embryonic stem cells can propagate indefinitely in a pluripotent state, able to differentiate into all types of specialized cells when restored to the embryo. What sustains their pluripotency during propagation remains unclear. Here, we show that core pluripotency factors OCT4 and SOX2 suppress chaperone-mediated autophagy (CMA), a selective form of autophagy, until the initiation of differentiation. Low CMA activity promotes embryonic stem cell self-renewal, whereas its up-regulation enhances differentiation. CMA degrades isocitrate dehydrogenases IDH1 and IDH2 and reduces levels of intracellular α-ketoglutarate, an obligatory cofactor for various histone and DNA demethylases involved in pluripotency. These findings suggest that CMA mediates the effect of core pluripotency factors on metabolism, shaping the epigenetic landscape of stem cells and governing the balance between self-renewal and differentiation.
    DOI:  https://doi.org/10.1126/science.abb4467
  16. Mol Cell. 2020 Jul 17. pii: S1097-2765(20)30467-6. [Epub ahead of print]
    Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.
    Marija Buljan, Rodolfo Ciuffa, Audrey van Drogen, Anton Vichalkovski, Martin Mehnert, George Rosenberger, Sohyon Lee, Markku Varjosalo, Lucia Espona Pernas, Vincent Spegg, Berend Snijder, Ruedi Aebersold, Matthias Gstaiger.
      Protein kinases are essential for signal transduction and control of most cellular processes, including metabolism, membrane transport, motility, and cell cycle. Despite the critical role of kinases in cells and their strong association with diseases, good coverage of their interactions is available for only a fraction of the 535 human kinases. Here, we present a comprehensive mass-spectrometry-based analysis of a human kinase interaction network covering more than 300 kinases. The interaction dataset is a high-quality resource with more than 5,000 previously unreported interactions. We extensively characterized the obtained network and were able to identify previously described, as well as predict new, kinase functional associations, including those of the less well-studied kinases PIM3 and protein O-mannose kinase (POMK). Importantly, the presented interaction map is a valuable resource for assisting biomedical studies. We uncover dozens of kinase-disease associations spanning from genetic disorders to complex diseases, including cancer.
    Keywords:  cancer; disease module; interaction network; kinome; protein complexes; protein kinases; proteomics; signaling regulation; systems biology
    DOI:  https://doi.org/10.1016/j.molcel.2020.07.001
  17. Science. 2020 Jul 24. 369(6502): 403-413
    The activities of drug inactive ingredients on biological targets.
    Joshua Pottel, Duncan Armstrong, Ling Zou, Alexander Fekete, Xi-Ping Huang, Hayarpi Torosyan, Dallas Bednarczyk, Steven Whitebread, Barun Bhhatarai, Guiqing Liang, Hong Jin, S Nassir Ghaemi, Samuel Slocum, Katalin V Lukacs, John J Irwin, Ellen L Berg, Kathleen M Giacomini, Bryan L Roth, Brian K Shoichet, Laszlo Urban.
      Excipients, considered "inactive ingredients," are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant K d values of 320 and 210 nM, respectively. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets.
    DOI:  https://doi.org/10.1126/science.aaz9906
  18. Cancer Cell. 2020 Jul 08. pii: S1535-6108(20)30316-0. [Epub ahead of print]
    Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.
    Nemanja Despot Marjanovic, Matan Hofree, Jason E Chan, David Canner, Katherine Wu, Marianna Trakala, Griffin G Hartmann, Olivia Smith, Jonathan Kim, Kelly Victoria Evans, Anna Hudson, Orr Ashenberg, Caroline B M Porter, Alborz Bejnood, Ayshwarya Subramanian, Kenneth Pitter, Yan Yan, Toni Delroy, Devan R Phillips, Nisargbhai Shah, Ojasvi Chaudhary, Alexander Tsankov, Travis Hollmann, Natasha Rekhtman, Pierre P Massion, John T Poirier, Linas Mazutis, Ruifang Li, Joo-Hyeon Lee, Angelika Amon, Charles M Rudin, Tyler Jacks, Aviv Regev, Tuomas Tammela.
      Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.
    Keywords:  cell state transition; lung cancer; plasticity; single-cell transcriptomics; tumor evolution; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.ccell.2020.06.012
  19. Nat Commun. 2020 Jul 20. 11(1): 3639
    Proteome activity landscapes of tumor cell lines determine drug responses.
    Martin Frejno, Chen Meng, Benjamin Ruprecht, Thomas Oellerich, Sebastian Scheich, Karin Kleigrewe, Enken Drecoll, Patroklos Samaras, Alexander Hogrebe, Dominic Helm, Julia Mergner, Jana Zecha, Stephanie Heinzlmeir, Mathias Wilhelm, Julia Dorn, Hans-Michael Kvasnicka, Hubert Serve, Wilko Weichert, Bernhard Kuster.
      Integrated analysis of genomes, transcriptomes, proteomes and drug responses of cancer cell lines (CCLs) is an emerging approach to uncover molecular mechanisms of drug action. We extend this paradigm to measuring proteome activity landscapes by acquiring and integrating quantitative data for 10,000 proteins and 55,000 phosphorylation sites (p-sites) from 125 CCLs. These data are used to contextualize proteins and p-sites and predict drug sensitivity. For example, we find that Progesterone Receptor (PGR) phosphorylation is associated with sensitivity to drugs modulating estrogen signaling such as Raloxifene. We also demonstrate that Adenylate kinase isoenzyme 1 (AK1) inactivates antimetabolites like Cytarabine. Consequently, high AK1 levels correlate with poor survival of Cytarabine-treated acute myeloid leukemia patients, qualifying AK1 as a patient stratification marker and possibly as a drug target. We provide an interactive web application termed ATLANTiC (http://atlantic.proteomics.wzw.tum.de), which enables the community to explore the thousands of novel functional associations generated by this work.
    DOI:  https://doi.org/10.1038/s41467-020-17336-9
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