bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2020–11–08
twenty-two papers selected by
Ralitsa Radostinova Madsen, University College London
  1. Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with PIK3CA-Mutant Cancers.
  2. Phosphatidylinositol-3-OH kinase signalling is spatially organized at endosomal compartments by microtubule-associated protein 4.
  3. TORC1 Determines Fab1 Lipid Kinase Function at Signaling Endosomes and Vacuoles.
  4. Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer.
  5. 3D Culture Models with CRISPR Screens Reveal Hyperactive NRF2 as a Prerequisite for Spheroid Formation via Regulation of Proliferation and Ferroptosis.
  6. The 3.2-Å resolution structure of human mTORC2.
  7. Large-Scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines.
  8. IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells.
  9. Amino Acids Enhance Polyubiquitination of Rheb and Its Binding to mTORC1 by Blocking Lysosomal ATXN3 Deubiquitinase Activity.
  10. Akt3 induces oxidative stress and DNA damage by activating the NADPH oxidase via phosphorylation of p47phox.
  11. mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline.
  12. Inositol-requiring enzyme-1 regulates phosphoinositide signaling lipids and macrophage growth.
  13. Setting the pick: Can PI3K inhibitors circumvent CDK 4/6 inhibitor resistance?
  14. eIF4E S209 phosphorylation licenses Myc-and stress-driven oncogenesis.
  15. netboxr: Automated discovery of biological process modules by network analysis in R.
  16. Combinatorial expression of GPCR isoforms affects signalling and drug responses.
  17. Class IA PI3Ks regulate subcellular and functional dynamics of IDO1.
  18. Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy.
  19. Insulin receptor substrate-1 (IRS-1) mediates progesterone receptor-driven stemness and endocrine resistance in oestrogen receptor+ breast cancer.
  20. A systematic review and meta-analysis of selected toxicity endpoints of alpelisib.
  21. A review on age-related cancer risks in PTEN Hamartoma Tumor Syndrome.
  22. Genomic control of metastasis.
  1. Clin Cancer Res. 2020 Nov 04. pii: clincanres.2657.2020. [Epub ahead of print]
    Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with PIK3CA-Mutant Cancers.
    Komal Jhaveri, Matthew T Chang, Dejan Juric, Cristina Saura, Valentina Gambardella, Anton Melnyk, Manish R Patel, Vincent Ribrag, Cynthia X Ma, Raid Aljumaily, Philippe L Bedard, Jasgit C Sachdev, Lara Dunn, Helen H Won, John Bond, Surai Jones, Heidi M Savage, Maurizio Scaltriti, Timothy R Wilson, Michael C Wei, David M Hyman.
       PURPOSE: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor, taselisib.
    PATIENTS AND METHODS: Patients were enrolled based on local PIK3CA mutation testing into 1 of 11 histology-specific cohorts and treated with taselisib at 6 mg or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed.
    RESULTS: 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9.0%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10.0%), and other cancers, plus tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and post-progression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index.
    CONCLUSIONS: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-2657
  2. Nat Cell Biol. 2020 Nov;22(11): 1357-1370
    Phosphatidylinositol-3-OH kinase signalling is spatially organized at endosomal compartments by microtubule-associated protein 4.
    Narendra Thapa, Mo Chen, Hudson T Horn, Suyong Choi, Tianmu Wen, Richard A Anderson.
      The canonical model of agonist-stimulated phosphatidylinositol-3-OH kinase (PI3K)-Akt signalling proposes that PI3K is activated at the plasma membrane, where receptors are activated and phosphatidylinositol-4,5-bisphosphate is concentrated. Here we show that phosphatidylinositol-3,4,5-trisphosphate generation and activated Akt are instead largely confined to intracellular membranes upon receptor tyrosine kinase activation. Microtubule-associated protein 4 (MAP4) interacts with and controls localization of membrane vesicle-associated PI3Kα to microtubules. The microtubule-binding domain of MAP4 binds directly to the C2 domain of the p110α catalytic subunit. MAP4 controls the interaction of PI3Kα with activated receptors at endosomal compartments along microtubules. Loss of MAP4 results in the loss of PI3Kα targeting and loss of PI3K-Akt signalling downstream of multiple agonists. The MAP4-PI3Kα assembly defines a mechanism for spatial control of agonist-stimulated PI3K-Akt signalling at internal membrane compartments linked to the microtubule network.
    DOI:  https://doi.org/10.1038/s41556-020-00596-4
  3. Curr Biol. 2020 Oct 30. pii: S0960-9822(20)31530-X. [Epub ahead of print]
    TORC1 Determines Fab1 Lipid Kinase Function at Signaling Endosomes and Vacuoles.
    Zilei Chen, Pedro Carpio Malia, Riko Hatakeyama, Raffaele Nicastro, Zehan Hu, Marie-Pierre Péli-Gulli, Jieqiong Gao, Taki Nishimura, Elja Eskes, Christopher J Stefan, Joris Winderickx, Jörn Dengjel, Claudio De Virgilio, Christian Ungermann.
      Organelles of the endomembrane system maintain their identity and integrity during growth or stress conditions by homeostatic mechanisms that regulate membrane flux and biogenesis. At lysosomes and endosomes, the Fab1 lipid kinase complex and the nutrient-regulated target of rapamycin complex 1 (TORC1) control the integrity of the endolysosomal homeostasis and cellular metabolism. Both complexes are functionally connected as Fab1-dependent generation of PI(3,5)P2 supports TORC1 activity. Here, we identify Fab1 as a target of TORC1 on signaling endosomes, which are distinct from multivesicular bodies, and provide mechanistic insight into their crosstalk. Accordingly, TORC1 can phosphorylate Fab1 proximal to its PI3P-interacting FYVE domain, which causes Fab1 to shift to signaling endosomes, where it generates PI(3,5)P2. This, in turn, regulates (1) vacuole morphology, (2) recruitment of TORC1 and the TORC1-regulatory Rag GTPase-containing EGO complex to signaling endosomes, and (3) TORC1 activity. Thus, our study unravels a regulatory feedback loop between TORC1 and the Fab1 complex that controls signaling at endolysosomes.
    Keywords:  Fab1; PI(3,5)P2; TORC1; cellular signaling; late endosome; lipid kinase; lysosome; phosphoinositide; signaling endosome; vacuole
    DOI:  https://doi.org/10.1016/j.cub.2020.10.026
  4. Breast Cancer Res. 2020 11 02. 22(1): 120
    Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer.
    Ana C Garrido-Castro, Cristina Saura, Romualdo Barroso-Sousa, Hao Guo, Eva Ciruelos, Begoña Bermejo, Joaquin Gavilá, Violeta Serra, Aleix Prat, Laia Paré, Pamela Céliz, Patricia Villagrasa, Yisheng Li, Jennifer Savoie, Zhan Xu, Carlos L Arteaga, Ian E Krop, David B Solit, Gordon B Mills, Lewis C Cantley, Eric P Winer, Nancy U Lin, Jordi Rodon.
       BACKGROUND: Treatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer.
    METHODS: This was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies.
    RESULTS: Fifty patients were enrolled. Median number of cycles was 2 (range 1-10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval [CI] 1.6-2.3). Median OS was 11.2 months (95% CI 6.2-25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease.
    CONCLUSIONS: Buparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer.
    TRIAL REGISTRATION: NCT01790932 . Registered on 13 February 2013; NCT01629615 . Registered on 27 June 2012.
    Keywords:  BKM120; Buparlisib; PI3K pathway; Phase 1; Triple-negative breast cancer
    DOI:  https://doi.org/10.1186/s13058-020-01354-y
  5. Mol Cell. 2020 Oct 26. pii: S1097-2765(20)30693-6. [Epub ahead of print]
    3D Culture Models with CRISPR Screens Reveal Hyperactive NRF2 as a Prerequisite for Spheroid Formation via Regulation of Proliferation and Ferroptosis.
    Nobuaki Takahashi, Patricia Cho, Laura M Selfors, Hendrik J Kuiken, Roma Kaul, Takuro Fujiwara, Isaac S Harris, Tian Zhang, Steven P Gygi, Joan S Brugge.
      Cancer-associated mutations that stabilize NRF2, an oxidant defense transcription factor, are predicted to promote tumor development. Here, utilizing 3D cancer spheroid models coupled with CRISPR-Cas9 screens, we investigate the molecular pathogenesis mediated by NRF2 hyperactivation. NRF2 hyperactivation was necessary for proliferation and survival in lung tumor spheroids. Antioxidant treatment rescued survival but not proliferation, suggesting the presence of distinct mechanisms. CRISPR screens revealed that spheroids are differentially dependent on the mammalian target of rapamycin (mTOR) for proliferation and the lipid peroxidase GPX4 for protection from ferroptosis of inner, matrix-deprived cells. Ferroptosis inhibitors blocked death from NRF2 downregulation, demonstrating a critical role of NRF2 in protecting matrix-deprived cells from ferroptosis. Interestingly, proteomics analyses show global enrichment of selenoproteins, including GPX4, by NRF2 downregulation, and targeting NRF2 and GPX4 killed spheroids overall. These results illustrate the value of spheroid culture in revealing environmental or spatial differential dependencies on NRF2 and reveal exploitable vulnerabilities of NRF2-hyperactivated tumors.
    Keywords:  oxidative stress, cancer, cell death, ferroptosis, 3D culture, NRF2, CRISPR screening, selenoprotein, GPX4
    DOI:  https://doi.org/10.1016/j.molcel.2020.10.010
  6. Sci Adv. 2020 Nov;pii: eabc1251. [Epub ahead of print]6(45):
    The 3.2-Å resolution structure of human mTORC2.
    Alain Scaiola, Francesca Mangia, Stefan Imseng, Daniel Boehringer, Karolin Berneiser, Mitsugu Shimobayashi, Edward Stuttfeld, Michael N Hall, Nenad Ban, Timm Maier.
      The protein kinase mammalian target of rapamycin (mTOR) is the central regulator of cell growth. Aberrant mTOR signaling is linked to cancer, diabetes, and neurological disorders. mTOR exerts its functions in two distinct multiprotein complexes, mTORC1 and mTORC2. Here, we report a 3.2-Å resolution cryo-EM reconstruction of mTORC2. It reveals entangled folds of the defining Rictor and the substrate-binding SIN1 subunits, identifies the carboxyl-terminal domain of Rictor as the source of the rapamycin insensitivity of mTORC2, and resolves mechanisms for mTORC2 regulation by complex destabilization. Two previously uncharacterized small-molecule binding sites are visualized, an inositol hexakisphosphate (InsP6) pocket in mTOR and an mTORC2-specific nucleotide binding site in Rictor, which also forms a zinc finger. Structural and biochemical analyses suggest that InsP6 and nucleotide binding do not control mTORC2 activity directly but rather have roles in folding or ternary interactions. These insights provide a firm basis for studying mTORC2 signaling and for developing mTORC2-specific inhibitors.
    DOI:  https://doi.org/10.1126/sciadv.abc1251
  7. Cancer Cell. 2020 Oct 26. pii: S1535-6108(20)30539-0. [Epub ahead of print]
    Large-Scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines.
    Wei Zhao, Jun Li, Mei-Ju M Chen, Yikai Luo, Zhenlin Ju, Nicole K Nesser, Katie Johnson-Camacho, Christopher T Boniface, Yancey Lawrence, Nupur T Pande, Michael A Davies, Meenhard Herlyn, Taru Muranen, Ioannis K Zervantonakis, Erika von Euw, Andre Schultz, Shwetha V Kumar, Anil Korkut, Paul T Spellman, Rehan Akbani, Dennis J Slamon, Joe W Gray, Joan S Brugge, Yiling Lu, Gordon B Mills, Han Liang.
      Perturbation biology is a powerful approach to modeling quantitative cellular behaviors and understanding detailed disease mechanisms. However, large-scale protein response resources of cancer cell lines to perturbations are not available, resulting in a critical knowledge gap. Here we generated and compiled perturbed expression profiles of ∼210 clinically relevant proteins in >12,000 cancer cell line samples in response to ∼170 drug compounds using reverse-phase protein arrays. We show that integrating perturbed protein response signals provides mechanistic insights into drug resistance, increases the predictive power for drug sensitivity, and helps identify effective drug combinations. We build a systematic map of "protein-drug" connectivity and develop a user-friendly data portal for community use. Our study provides a rich resource to investigate the behaviors of cancer cells and the dependencies of treatment responses, thereby enabling a broad range of biomedical applications.
    Keywords:  biomarker; cancer signaling pathway; drug response; protein array
    DOI:  https://doi.org/10.1016/j.ccell.2020.10.008
  8. Nature. 2020 Nov 04.
    IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells.
    Jaewoong Lee, Mark E Robinson, Ning Ma, Dewan Artadji, Mohamed A Ahmed, Gang Xiao, Teresa Sadras, Gauri Deb, Janet Winchester, Kadriye Nehir Cosgun, Huimin Geng, Lai N Chan, Kohei Kume, Teemu P Miettinen, Ye Zhang, Matthew A Nix, Lars Klemm, Chun Wei Chen, Jianjun Chen, Vishal Khairnar, Arun P Wiita, Andrei Thomas-Tikhonenko, Michael Farzan, Jae U Jung, David M Weinstock, Scott R Manalis, Michael S Diamond, Nagarajan Vaidehi, Markus Müschen.
      Interferon-induced transmembrane protein 3 (IFITM3) has previously been identified as an endosomal protein that blocks viral infection1-3. Here we studied clinical cohorts of patients with B cell leukaemia and lymphoma, and identified IFITM3 as a strong predictor of poor outcome. In normal resting B cells, IFITM3 was minimally expressed and mainly localized in endosomes. However, engagement of the B cell receptor (BCR) induced both expression of IFITM3 and phosphorylation of this protein at Tyr20, which resulted in the accumulation of IFITM3 at the cell surface. In B cell leukaemia, oncogenic kinases phosphorylate IFITM3 at Tyr20, which causes constitutive localization of this protein at the plasma membrane. In a mouse model, Ifitm3-/- naive B cells developed in normal numbers; however, the formation of germinal centres and the production of antigen-specific antibodies were compromised. Oncogenes that induce the development of leukaemia and lymphoma did not transform Ifitm3-/- B cells. Conversely, the phosphomimetic IFITM3(Y20E) mutant induced oncogenic PI3K signalling and initiated the transformation of premalignant B cells. Mechanistic experiments revealed that IFITM3 functions as a PIP3 scaffold and central amplifier of PI3K signalling. The amplification of PI3K signals depends on IFITM3 using two lysine residues (Lys83 and Lys104) in its conserved intracellular loop as a scaffold for the accumulation of PIP3. In Ifitm3-/- B cells, lipid rafts were depleted of PIP3, which resulted in the defective expression of over 60 lipid-raft-associated surface receptors, and impaired BCR signalling and cellular adhesion. We conclude that the phosphorylation of IFITM3 that occurs after B cells encounter antigen induces a dynamic switch from antiviral effector functions in endosomes to a PI3K amplification loop at the cell surface. IFITM3-dependent amplification of PI3K signalling, which in part acts downstream of the BCR, is critical for the rapid expansion of B cells with high affinity to antigen. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signalling complexes and amplify PI3K signalling for malignant transformation.
    DOI:  https://doi.org/10.1038/s41586-020-2884-6
  9. Mol Cell. 2020 Nov 05. pii: S1097-2765(20)30687-0. [Epub ahead of print]80(3): 437-451.e6
    Amino Acids Enhance Polyubiquitination of Rheb and Its Binding to mTORC1 by Blocking Lysosomal ATXN3 Deubiquitinase Activity.
    Yao Yao, Sungki Hong, Takayuki Ikeda, Hiroyuki Mori, Ormond A MacDougald, Shigeyuki Nada, Masato Okada, Ken Inoki.
      Amino-acid-induced lysosomal mechanistic target of rapamycin complex 1 (mTORC1) localization through the Rag GTPases is a critical step for its activation by Rheb GTPase. However, how the mTORC1 interacts with Rheb on the lysosome remains elusive. We report that amino acids enhance the polyubiquitination of Rheb (Ub-Rheb), which shows a strong binding preference for mTORC1 and supports its activation, while the Ub-Rheb is subjected to subsequent degradation. Mechanistically, we identified ATXN3 as a Ub-Rheb deubiquitinase whose lysosomal localization is blocked by active Rag heterodimer in response to amino acid stimulation. Consistently, cells lacking functional Rag heterodimer on the lysosome accumulate Ub-Rheb, and blockade of its degradation instigates robust lysosomal mTORC1 localization and its activation without the Ragulator-Rag system. Thus, polyubiquitination of Rheb is an important post-translational modification, which facilitates the binding of mTORC1 to Rheb on the lysosome and is another crosstalk between the amino acid and growth factor signaling for mTORC1 activation.
    Keywords:  ATXN3; Rag; Ragulator; Rheb; amino acids; deubiquitination; lysosome; mTORC1; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2020.10.004
  10. Proc Natl Acad Sci U S A. 2020 Nov 02. pii: 202017830. [Epub ahead of print]
    Akt3 induces oxidative stress and DNA damage by activating the NADPH oxidase via phosphorylation of p47phox.
    Christos Polytarchou, Maria Hatziapostolou, Tung On Yau, Niki Christodoulou, Philip W Hinds, Filippos Kottakis, Ioannis Sanidas, Philip N Tsichlis.
      Akt activation up-regulates the intracellular levels of reactive oxygen species (ROS) by inhibiting ROS scavenging. Of the Akt isoforms, Akt3 has also been shown to up-regulate ROS by promoting mitochondrial biogenesis. Here, we employ a set of isogenic cell lines that express different Akt isoforms, to show that the most robust inducer of ROS is Akt3. As a result, Akt3-expressing cells activate the DNA damage response pathway, express high levels of p53 and its direct transcriptional target miR-34, and exhibit a proliferation defect, which is rescued by the antioxidant N-acetylcysteine. The importance of the DNA damage response in the inhibition of cell proliferation by Akt3 was confirmed by Akt3 overexpression in p53 -/- and INK4a -/-/Arf -/- mouse embryonic fibroblasts (MEFs), which failed to inhibit cell proliferation, despite the induction of high levels of ROS. The induction of ROS by Akt3 is due to the phosphorylation of the NADPH oxidase subunit p47phox, which results in NADPH oxidase activation. Expression of Akt3 in p47 phox-/- MEFs failed to induce ROS and to inhibit cell proliferation. Notably, the proliferation defect was rescued by wild-type p47phox, but not by the phosphorylation site mutant of p47phox In agreement with these observations, Akt3 up-regulates p53 in human cancer cell lines, and the expression of Akt3 positively correlates with the levels of p53 in a variety of human tumors. More important, Akt3 alterations correlate with a higher frequency of mutation of p53, suggesting that tumor cells may adapt to high levels of Akt3, by inactivating the DNA damage response.
    Keywords:  Akt isoforms; DNA damage; NADPH oxidase; cancer; oxidative stress
    DOI:  https://doi.org/10.1073/pnas.2017830117
  11. Nat Commun. 2020 Nov 06. 11(1): 5640
    mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline.
    Kseniya Obraztsova, Maria C Basil, Ryan Rue, Aravind Sivakumar, Susan M Lin, Alexander R Mukhitov, Andrei I Gritsiuta, Jilly F Evans, Meghan Kopp, Jeremy Katzen, Annette Robichaud, Elena N Atochina-Vasserman, Shanru Li, Justine Carl, Apoorva Babu, Michael P Morley, Edward Cantu, Michael F Beers, David B Frank, Edward E Morrisey, Vera P Krymskaya.
      Lymphangioleiomyomatosis (LAM) is a rare fatal cystic lung disease due to bi-allelic inactivating mutations in tuberous sclerosis complex (TSC1/TSC2) genes coding for suppressors of the mechanistic target of rapamycin complex 1 (mTORC1). The origin of LAM cells is still unknown. Here, we profile a LAM lung compared to an age- and sex-matched healthy control lung as a hypothesis-generating approach to identify cell subtypes that are specific to LAM. Our single-cell RNA sequencing (scRNA-seq) analysis reveals novel mesenchymal and transitional alveolar epithelial states unique to LAM lung. This analysis identifies a mesenchymal cell hub coordinating the LAM disease phenotype. Mesenchymal-restricted deletion of Tsc2 in the mouse lung produces a mTORC1-driven pulmonary phenotype, with a progressive disruption of alveolar structure, a decline in pulmonary function, increase of rapamycin-sensitive expression of WNT ligands, and profound female-specific changes in mesenchymal and epithelial lung cell gene expression. Genetic inactivation of WNT signaling reverses age-dependent changes of mTORC1-driven lung phenotype, but WNT activation alone in lung mesenchyme is not sufficient for the development of mouse LAM-like phenotype. The alterations in gene expression are driven by distinctive crosstalk between mesenchymal and epithelial subsets of cells observed in mesenchymal Tsc2-deficient lungs. This study identifies sex- and age-specific gene changes in the mTORC1-activated lung mesenchyme and establishes the importance of the WNT signaling pathway in the mTORC1-driven lung phenotype.
    DOI:  https://doi.org/10.1038/s41467-020-18979-4
  12. EMBO Rep. 2020 Nov 02. e51462
    Inositol-requiring enzyme-1 regulates phosphoinositide signaling lipids and macrophage growth.
    Syed Muhammad Hamid, Mevlut Citir, Erdem Murat Terzi, Ismail Cimen, Zehra Yildirim, Asli Ekin Dogan, Begum Kocaturk, Umut Inci Onat, Moshe Arditi, Christian Weber, Alexis Traynor-Kaplan, Carsten Schultz, Ebru Erbay.
      The ER-bound kinase/endoribonuclease (RNase), inositol-requiring enzyme-1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1's one known, specific RNA target, X box-binding protein-1 (XBP1) or the RNA substrates of IRE1-dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide-derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross-talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1's RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P3 ) 5-phosphatase-2 (INPPL1) is a direct target of miR-2137, which controls PI(3,4,5)P3 levels in macrophages. The modulation of cellular PI(3,4,5)P3 /PIP2 ratio and anabolic mTOR signaling by the IRE1-induced miR-2137 demonstrates how the ER can provide a critical input into cell growth decisions.
    Keywords:  ER stress; hyperlipidemia; mTOR signaling; macrophage; microRNA
    DOI:  https://doi.org/10.15252/embr.202051462
  13. Clin Cancer Res. 2020 Nov 03. pii: clincanres.3624.2020. [Epub ahead of print]
    Setting the pick: Can PI3K inhibitors circumvent CDK 4/6 inhibitor resistance?
    Amy S Clark, Igor Makhlin, Angela DeMichele.
      PI3K and CDK 4/6 inhibitors are targeted therapies approved to treat advanced breast cancer; CDK 4/6 inhibitors are more widely used. Here we discuss trials that examine PI3K inhibitors with novel drug combinations including a CDK 4/6 inhibitor given data implicating the pathway in CDK 4/6 resistance.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-3624
  14. Elife. 2020 Nov 02. pii: e60151. [Epub ahead of print]9
    eIF4E S209 phosphorylation licenses Myc-and stress-driven oncogenesis.
    Hang Ruan, Xiangyun Li, Xiang Xu, Brian J Leibowitz, Jingshan Tong, Lujia Chen, Luoquan Ao, Wei Xing, Jianhua Luo, Yanping Yu, Robert E Schoen, Nahum Sonenberg, Xinghua Lu, Lin Zhang, Jian Yu.
      To better understand a role of eIF4E S209 in oncogenic translation, we generated EIF4ES209A/+ heterozygous knockin (4EKI) HCT 116 human colorectal cancer (CRC) cells. 4EKI had little on total eIF4E levels, cap binding or global translation, while markedly reduced HCT 116 cell growth in spheroids and mice, and CRC organoid growth. 4EKI strongly inhibited Myc and ATF4 translation, the integrated Stress Response (ISR)-dependent glutamine metabolic signature, AKT activation and proliferation in vivo. 4EKI inhibited polyposis in ApcMin/+ mice by suppressing Myc protein and AKT activation. Furthermore, p-eIF4E was highly elevated in CRC precursor lesions in mouse and human. p-eIF4E cooperated with mutant KRAS to promote Myc and ISR-dependent glutamine addiction in various CRC cell lines, characterized by increased cell death, transcriptomic heterogeneity and immune suppression upon deprivation. These findings demonstrate a critical role of eIF4E S209-dependent translation in Myc and stress-driven oncogenesis and as a potential therapeutic vulnerability.
    Keywords:  cancer biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.60151
  15. PLoS One. 2020 ;15(11): e0234669
    netboxr: Automated discovery of biological process modules by network analysis in R.
    Eric Minwei Liu, Augustin Luna, Guanlan Dong, Chris Sander.
       SUMMARY: Large-scale sequencing projects, such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), have generated high throughput sequencing and molecular profiling data sets, but it is still challenging to identify potentially causal changes in cellular processes in cancer as well as in other diseases in an automated fashion. We developed the netboxr package written in the R programming language, which makes use of the NetBox algorithm to identify candidate cancer-related functional modules. The algorithm makes use of a data-driven, network-based approach that combines prior knowledge with a network clustering algorithm, obviating the need for and the limitation of independently curated functionally labeled gene sets. The method can combine multiple data types, such as mutations and copy number alterations, leading to more reliable identification of functional modules. We make the tool available in the Bioconductor R ecosystem for applications in cancer research and cell biology.
    AVAILABILITY AND IMPLEMENTATION: The netboxr package is free and open-sourced under the GNU GPL-3 license R package available at https://www.bioconductor.org/packages/release/bioc/html/netboxr.html.
    DOI:  https://doi.org/10.1371/journal.pone.0234669
  16. Nature. 2020 Nov 04.
    Combinatorial expression of GPCR isoforms affects signalling and drug responses.
    Maria Marti-Solano, Stephanie E Crilly, Duccio Malinverni, Christian Munk, Matthew Harris, Abigail Pearce, Tezz Quon, Amanda E Mackenzie, Xusheng Wang, Junmin Peng, Andrew B Tobin, Graham Ladds, Graeme Milligan, David E Gloriam, Manojkumar A Puthenveedu, M Madan Babu.
      G-protein-coupled receptors (GPCRs) are membrane proteins that modulate physiology across human tissues in response to extracellular signals. GPCR-mediated signalling can differ because of changes in the sequence1,2 or expression3 of the receptors, leading to signalling bias when comparing diverse physiological systems4. An underexplored source of such bias is the generation of functionally diverse GPCR isoforms with different patterns of expression across different tissues. Here we integrate data from human tissue-level transcriptomes, GPCR sequences and structures, proteomics, single-cell transcriptomics, population-wide genetic association studies and pharmacological experiments. We show how a single GPCR gene can diversify into several isoforms with distinct signalling properties, and how unique isoform combinations expressed in different tissues can generate distinct signalling states. Depending on their structural changes and expression patterns, some of the detected isoforms may influence cellular responses to drugs and represent new targets for developing drugs with improved tissue selectivity. Our findings highlight the need to move from a canonical to a context-specific view of GPCR signalling that considers how combinatorial expression of isoforms in a particular cell type, tissue or organism collectively influences receptor signalling and drug responses.
    DOI:  https://doi.org/10.1038/s41586-020-2888-2
  17. EMBO Rep. 2020 Nov 07. e49756
    Class IA PI3Ks regulate subcellular and functional dynamics of IDO1.
    Alberta Iacono, Andrea Pompa, Francesca De Marchis, Eleonora Panfili, Francesco A Greco, Alice Coletti, Ciriana Orabona, Claudia Volpi, Maria L Belladonna, Giada Mondanelli, Elisa Albini, Carmine Vacca, Marco Gargaro, Francesca Fallarino, Roberta Bianchi, Carine De Marcos Lousa, Emilia Mc Mazza, Silvio Bicciato, Elisa Proietti, Francesca Milano, Maria P Martelli, Ioana M Iamandii, Mariona Graupera Garcia-Mila, Judith Llena Sopena, Phillip Hawkins, Sabine Suire, Klaus Okkenhaug, Anne-Katrien Stark, Fabio Grassi, Michele Bellucci, Paolo Puccetti, Laura Santambrogio, Antonio Macchiarulo, Ursula Grohmann, Maria T Pallotta.
      Knowledge of a protein's spatial dynamics at the subcellular level is key to understanding its function(s), interactions, and associated intracellular events. Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic enzyme that controls immune responses via tryptophan metabolism, mainly through its enzymic activity. When phosphorylated, however, IDO1 acts as a signaling molecule in plasmacytoid dendritic cells (pDCs), thus activating genomic effects, ultimately leading to long-lasting immunosuppression. Whether the two activities-namely, the catalytic and signaling functions-are spatially segregated has been unclear. We found that, under conditions favoring signaling rather than catabolic events, IDO1 shifts from the cytosol to early endosomes. The event requires interaction with class IA phosphoinositide 3-kinases (PI3Ks), which become activated, resulting in full expression of the immunoregulatory phenotype in vivo in pDCs as resulting from IDO1-dependent signaling events. Thus, IDO1's spatial dynamics meet the needs for short-acting as well as durable mechanisms of immune suppression, both under acute and chronic inflammatory conditions. These data expand the theoretical basis for an IDO1-centered therapy in inflammation and autoimmunity.
    Keywords:  dendritic cells; early endosomes; indoleamine 2,3-dioxygenase 1 (IDO1); phosphoinositide 3-kinase (PI3K); tryptophan metabolism
    DOI:  https://doi.org/10.15252/embr.201949756
  18. Cancer Discov. 2020 Nov 02.
    Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy.
    Sarah-Maria Fendt, Christian Frezza, Ayelet Erez.
      Cancer cells continuously rewire their metabolism to fulfill their need for rapid growth and survival while subject to changes in environmental cues. Thus, a vital component of a cancer cell lies in its metabolic adaptability. The constant demand for metabolic alterations requires flexibility, that is, the ability to utilize different metabolic substrates; as well as plasticity, that is, the ability to process metabolic substrates in different ways. In this review, we discuss how dynamic changes in cancer metabolism affect tumor progression and the consequential implications for cancer therapy. SIGNIFICANCE: Recognizing cancer dynamic metabolic adaptability as an entity can lead to targeted therapy that is expected to decrease drug resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0844
  19. Br J Cancer. 2020 Nov 04.
    Insulin receptor substrate-1 (IRS-1) mediates progesterone receptor-driven stemness and endocrine resistance in oestrogen receptor+ breast cancer.
    Amy R Dwyer, Thu H Truong, Carlos Perez Kerkvliet, Kiran V Paul, Peter Kabos, Carol A Sartorius, Carol A Lange.
       BACKGROUND: Progesterone receptors (PR) are potent modifiers of endocrine responses. In aberrant signalling cancer contexts, phosphorylation events dramatically alter steroid hormone receptor action.
    METHODS: The transcriptomes of primary tumours and metastases in mice harbouring ER+ breast cancer patient-derived xenografts (PDXs) were analysed following single-cell RNAseq. In vitro assays were employed to delineate mechanisms of endocrine resistance and stemness.
    RESULTS: A 16-gene phospho-Ser294 PR (p-PR) signature predicted poor outcome in ER+ breast cancer. Relative to primary PDX tumours, metastatic lesions expressed abundant p-PR and exhibited an activated PR gene programme with elevated expression of PGR and IRS-1. Breast cancer models of activated PR lost the expression of IGF1R and acquired insulin hypersensitivity with tamoxifen insensitivity. Activated p-PR+ breast cancer cells formed increased tumourspheres with enlarged ALDH+ and CD24-/CD44 populations. E2 induced PR/IRS-1 interaction and exchange of IGF1Rβ for IRS-1 in p-PR-containing transcriptional complexes. Inhibition of IRS-1 or IR and inducible IRS-1 knockdown reduced tumourspheres. Endocrine-resistant models of luminal B breast cancer induced p-PR in 3D cultures and required PR and IRS-1 for tumoursphere formation.
    CONCLUSIONS: Phospho-PR-B cooperates with IRS-1 to promote outgrowth of endocrine-resistant and stem-like breast cancer cells. Targeting phospho-PR/IRS-1 crosstalk may block the emergence of endocrine resistance.
    DOI:  https://doi.org/10.1038/s41416-020-01094-y
  20. Oncotarget. 2020 Oct 20. 11(42): 3793-3799
    A systematic review and meta-analysis of selected toxicity endpoints of alpelisib.
    Misty Shields, Qianxing Mo, Melissa Armitage, Susan C Sharpe, Ricardo L B Costa.
       PURPOSE: Alpelisib is a first-in-class α-specific phosphatidylinositol 3-kinase inhibitor approved for the treatment of patients with estrogen receptor-positive metastatic breast cancer. High absolute risk (AR) of relevant toxicities has been observed with this treatment. This meta-analysis aimed to improve the precision of the estimated AR of selected adverse events (AEs) associated with this new agent.
    MATERIALS AND METHODS: A literature search was conducted in August 2019 to identify trials analyzing the anti-tumor efficacy and toxicity profile of alpelisib. Heterogeneity was assessed by using I 2 statistics. Data were analyzed using random effect meta-analyses for AR. Eleven trials and 511 patients were included.
    RESULTS: There was no evidence of heterogeneity between studies regarding the AR of most AEs except for all-grade weight loss and grade 3-4 stomatitis. The number of serious AEs was clearly reported in only one study, of which the most common was hyperglycemia; the most common all-grade AEs were hyperglycemia (59%), diarrhea (56%), nausea (44%), and rash (38%). Grade 3/4 hyperglycemia and rash occurred in 28% and 10% of patients, respectively. No treatment-associated deaths were observed, and 18% of patients had to stop treatment due to toxicities.
    CONCLUSIONS: Alpelisib is associated with clinically relevant AEs that can lead to treatment discontinuation. The most common AE was hyperglycemia. No treatment-related deaths were observed.
    Keywords:  adverse event; alpelisib; diarrhea; hyperglycemia; rash
    DOI:  https://doi.org/10.18632/oncotarget.27770
  21. Clin Genet. 2020 Nov 02.
    A review on age-related cancer risks in PTEN Hamartoma Tumor Syndrome.
    Linda A J Hendricks, Nicoline Hoogerbrugge, Janneke H M Schuurs-Hoeijmakers, Janet R Vos.
      Patients with PTEN Hamartoma Tumor Syndrome (PHTS, comprising Cowden, Bannayan-Riley-Ruvalcaba, and Proteus-like syndromes) are at increased risk of developing cancer due to pathogenic PTEN germline variants. This review summarizes age-, sex- and type-specific malignant cancer risks for PHTS patients, which is urgently needed for clinical management. A PubMed literature search for Standardized Incidence Ratios or Cumulative Lifetime cancer risks (CLTRs) resulted in nine cohort studies comprising four independent PHTS cohorts, including mainly index cases and prevalent cancer cases. The median age at diagnosis was 36 years. Reported CLTRs for any cancer varied from 81% to 90%. The tumor spectrum included female breast cancer (CLTRs including sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19% to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal cancer (9% to 32%), and melanoma (0% to 6%). Although these estimates provide guidance for clinical care, discrepancies between studies, sample sizes, retrospective designs, strongly ascertained cases, and lack of pediatric research emphasizes that data should be interpreted with great caution. Therefore, more accurate and more personalized age-, sex- and cancer-specific risk estimates are needed to enable counseling of all PHTS patients irrespective of ascertainment, and improvement of cancer surveillance guidelines. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1111/cge.13875
  22. Br J Cancer. 2020 Nov 04.
    Genomic control of metastasis.
    Saroor A Patel, Paulo Rodrigues, Ludovic Wesolowski, Sakari Vanharanta.
      Metastasis remains the leading cause of cancer-associated mortality, and a detailed understanding of the metastatic process could suggest new therapeutic avenues. However, how metastatic phenotypes arise at the genomic level has remained a major open question in cancer biology. Comparative genetic studies of primary and metastatic cancers have revealed a complex picture of metastatic evolution with diverse temporal patterns and trajectories to dissemination. Whole-genome amplification is associated with metastatic cancer clones, but no metastasis-exclusive driver mutations have emerged. Instead, genetically activated oncogenic pathways that drive tumour initiation and early progression acquire metastatic traits by co-opting physiological programmes from stem cell, developmental and regenerative pathways. The functional consequences of oncogenic driver mutations therefore change via epigenetic mechanisms to promote metastasis. Increasing evidence is starting to uncover the molecular mechanisms that determine how specific oncogenic drivers interact with various physiological programmes, and what triggers their activation in support of metastasis. Detailed insight into the mechanisms that control metastasis is likely to reveal novel opportunities for intervention at different stages of metastatic progression.
    DOI:  https://doi.org/10.1038/s41416-020-01127-6
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