bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2021–04–25
eleven papers selected by
Ralitsa Radostinova Madsen, University College London
  1. Hypoglycemia due to PI3K/AKT/mTOR signaling pathway defects: two novel cases and review of the literature.
  2. Distinct signaling by insulin and IGF-1 receptors and their extra- and intracellular domains.
  3. 4E-BP2-dependent translation in parvalbumin neurons controls epileptic seizure threshold.
  4. Insulin Actions on the Vascular Tissues: Physiological Effects and Pathophysiological Contributions to Vascular Complications of Diabetes.
  5. Disruption of the HER3-PI3K-mTOR oncogenic signaling axis and PD-1 blockade as a multimodal precision immunotherapy in head and neck cancer.
  6. DAF-16/FoxO and DAF-12/VDR control cellular plasticity both cell-autonomously and via interorgan signaling.
  7. Genomic profile of advanced breast cancer in circulating tumour DNA.
  8. PTEN loss correlates with T cell exclusion across human cancers.
  9. Pharmacological and cell-specific genetic PI3Kα inhibition worsens cardiac remodeling after myocardial infarction.
  10. Glucose deprivation induced aberrant FUT1-mediated fucosylation drives cancer stemness in hepatocellular carcinoma.
  11. Copanlisib safe and active in combination.
  1. Hormones (Athens). 2021 Apr 20.
    Hypoglycemia due to PI3K/AKT/mTOR signaling pathway defects: two novel cases and review of the literature.
    Evelina Maines, Roberto Franceschi, Diego Martinelli, Fiorenza Soli, Francesca Romana Lepri, Giovanni Piccoli, Massimo Soffiati.
       INTRODUCTION: The PI3K/AKT/mTOR signaling pathway is important for the regulation of multiple biological processes, including cellular growth and glucose metabolism. Defects of the PI3K/AKT/mTOR signaling pathway are not usually considered among the genetic causes of recurrent hypoglycemia in childhood. However, accumulating evidence links hypoglycemia with defects of this pathway.
    CASE REPORTS AND REVIEW: We describe here two cases of macrocephaly and hypoglycemia bearing genetic defects in genes involved in the PI3K/AKT/mTOR pathway. The first patient was diagnosed with a PTEN hamartoma tumour syndrome (PTHS) due to the de novo germline missense mutation c.[492 + 1G > A] of the PTEN gene. The second patient presented the autosomal dominant mental retardation-35 (MDR35) due to the heterozygous missense mutation c.592G > A in the PPP2R5D gene. A review of the literature on hypoglycemia and PI3K/AKT/mTOR signaling pathway defects, with a special focus on the metabolic characterization of hypoglycemia, is included.
    CONCLUSIONS: PI3K/AKT/mTOR pathway defects should be included in the differential diagnosis of patients with hypoglycemia and macrocephaly. Clinical suspicion and molecular confirmation are important, not just for an accurate genetic counselling but also for defining the follow-up management, including cancer surveillance. The biochemical profile of hypoglycemia varies among patients. While most patients are characterized by low plasmatic insulin levels, hyperinsulinemia has also been observed. Large patient cohorts are needed to gain a comprehensive profile of the biochemical patterns of hypoglycemia in such defects and eventually guide targeted therapeutic interventions.
    Keywords:  Hypoglycemia; Macrocephaly; Overgrowth; PI3K/AKT/mTOR signaling pathway; Review
    DOI:  https://doi.org/10.1007/s42000-021-00287-1
  2. Proc Natl Acad Sci U S A. 2021 Apr 27. pii: e2019474118. [Epub ahead of print]118(17):
    Distinct signaling by insulin and IGF-1 receptors and their extra- and intracellular domains.
    Hirofumi Nagao, Weikang Cai, Nicolai J Wewer Albrechtsen, Martin Steger, Thiago M Batista, Hui Pan, Jonathan M Dreyfuss, Matthias Mann, C Ronald Kahn.
      Insulin and insulin-like growth factor 1 (IGF-1) receptors share many downstream signaling pathways but have unique biological effects. To define the molecular signals contributing to these distinct activities, we performed global phosphoproteomics on cells expressing either insulin receptor (IR), IGF-1 receptor (IGF1R), or chimeric IR-IGF1R receptors. We show that IR preferentially stimulates phosphorylations associated with mammalian target of rapamycin complex 1 (mTORC1) and Akt pathways, whereas IGF1R preferentially stimulates phosphorylations on proteins associated with the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases), and cell cycle progression. There were also major differences in the phosphoproteome between cells expressing IR versus IGF1R in the unstimulated state, including phosphorylation of proteins involved in membrane trafficking, chromatin remodeling, and cell cycle. In cells expressing chimeric IR-IGF1R receptors, these differences in signaling could be mapped to contributions of both the extra- and intracellular domains of these receptors. Thus, despite their high homology, IR and IGF1R preferentially regulate distinct networks of phosphorylation in both the basal and stimulated states, allowing for the unique effects of these hormones on organismal function.
    Keywords:  IGF-1 signaling; cellular signaling; insulin signaling; kinases; protein phosphorylation
    DOI:  https://doi.org/10.1073/pnas.2019474118
  3. Proc Natl Acad Sci U S A. 2021 Apr 13. pii: e2025522118. [Epub ahead of print]118(15):
    4E-BP2-dependent translation in parvalbumin neurons controls epileptic seizure threshold.
    Vijendra Sharma, Rapita Sood, Danning Lou, Tzu-Yu Hung, Maxime Lévesque, Yelin Han, Jeremy Y Levett, Peng Wang, Shravan Murthy, Shannon Tansley, Siyan Wang, Nadeem Siddiqui, Soroush Tahmasebi, Kobi Rosenblum, Massimo Avoli, Jean-Claude Lacaille, Nahum Sonenberg, Arkady Khoutorsky.
      The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)-induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3ca H1047R-Pvalb ) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.
    Keywords:  epilepsy; mRNA translation; mTORC1
    DOI:  https://doi.org/10.1073/pnas.2025522118
  4. Mol Metab. 2021 Apr 17. pii: S2212-8778(21)00081-8. [Epub ahead of print] 101236
    Insulin Actions on the Vascular Tissues: Physiological Effects and Pathophysiological Contributions to Vascular Complications of Diabetes.
    Jialin Fu, Marc Gregory Yu, Qian Li, Kyoungmin Park, George L King.
       BACKGROUND: Insulin has been demonstrated to exert direct and indirect effects on vascular tissues. Its actions in vascular cells are mediated by two major pathways: The insulin receptor substrate 1/2-phosphoinositide-3 kinase/Akt (IRS1/2/PI3K/Akt) pathway and the Src/mitogen-activated protein kinase (MAPK) pathway, both of which contribute to the expression and distribution of metabolites, hormones and cytokines.
    SCOPE OF REVIEW: In this review, we summarize the current understanding on insulin's physiological and pathophysiological actions and associated signaling pathways in vascular cells, mainly in endothelial cells (EC) and vascular smooth muscle cells (VSMC), and how these processes lead to selective insulin resistance. We will also describe insulin's potential new signaling and biological effects derived from animal studies and cultured capillary and arterial EC, VSMC and pericytes. We will not provide a detailed discussion of insulin's effects on the myocardium, or of insulin structure or the various steps of its signaling pathways, since other articles in this issue will be discussing these areas in depth.
    Keywords:  CVD; cardiovascular complications; diabetes; insulin resistance
    DOI:  https://doi.org/10.1016/j.molmet.2021.101236
  5. Nat Commun. 2021 Apr 22. 12(1): 2383
    Disruption of the HER3-PI3K-mTOR oncogenic signaling axis and PD-1 blockade as a multimodal precision immunotherapy in head and neck cancer.
    Zhiyong Wang, Yusuke Goto, Michael M Allevato, Victoria H Wu, Robert Saddawi-Konefka, Mara Gilardi, Diego Alvarado, Bryan S Yung, Aoife O'Farrell, Alfredo A Molinolo, Umamaheswar Duvvuri, Jennifer R Grandis, Joseph A Califano, Ezra E W Cohen, J Silvio Gutkind.
      Immune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors may limit the benefit of their combination with ICB. Here we employ an unbiased kinome-wide siRNA screen to reveal that HER3, is essential for the proliferation of most HNSCC cells that do not harbor PIK3CA mutations. Indeed, we find that persistent tyrosine phosphorylation of HER3 and PI3K recruitment underlies aberrant PI3K/AKT/mTOR signaling in PIK3CA wild type HNSCCs. Remarkably, antibody-mediated HER3 blockade exerts a potent anti-tumor effect by suppressing HER3-PI3K-AKT-mTOR oncogenic signaling and concomitantly reversing the immune suppressive tumor microenvironment. Ultimately, we show that HER3 inhibition and PD-1 blockade may provide a multimodal precision immunotherapeutic approach for PIK3CA wild type HNSCC, aimed at achieving durable cancer remission.
    DOI:  https://doi.org/10.1038/s41467-021-22619-w
  6. PLoS Biol. 2021 Apr 23. 19(4): e3001204
    DAF-16/FoxO and DAF-12/VDR control cellular plasticity both cell-autonomously and via interorgan signaling.
    Ulkar Aghayeva, Abhishek Bhattacharya, Surojit Sural, Eliza Jaeger, Matthew Churgin, Christopher Fang-Yen, Oliver Hobert.
      Many cell types display the remarkable ability to alter their cellular phenotype in response to specific external or internal signals. Such phenotypic plasticity is apparent in the nematode Caenorhabditis elegans when adverse environmental conditions trigger entry into the dauer diapause stage. This entry is accompanied by structural, molecular, and functional remodeling of a number of distinct tissue types of the animal, including its nervous system. The transcription factor (TF) effectors of 3 different hormonal signaling systems, the insulin-responsive DAF-16/FoxO TF, the TGFβ-responsive DAF-3/SMAD TF, and the steroid nuclear hormone receptor, DAF-12/VDR, a homolog of the vitamin D receptor (VDR), were previously shown to be required for entering the dauer arrest stage, but their cellular and temporal focus of action for the underlying cellular remodeling processes remained incompletely understood. Through the generation of conditional alleles that allowed us to spatially and temporally control gene activity, we show here that all 3 TFs are not only required to initiate tissue remodeling upon entry into the dauer stage, as shown before, but are also continuously required to maintain the remodeled state. We show that DAF-3/SMAD is required in sensory neurons to promote and then maintain animal-wide tissue remodeling events. In contrast, DAF-16/FoxO or DAF-12/VDR act cell-autonomously to control anatomical, molecular, and behavioral remodeling events in specific cell types. Intriguingly, we also uncover non-cell autonomous function of DAF-16/FoxO and DAF-12/VDR in nervous system remodeling, indicating the presence of several insulin-dependent interorgan signaling axes. Our findings provide novel perspectives into how hormonal systems control tissue remodeling.
    DOI:  https://doi.org/10.1371/journal.pbio.3001204
  7. Nat Commun. 2021 Apr 23. 12(1): 2423
    Genomic profile of advanced breast cancer in circulating tumour DNA.
    Belinda Kingston, Rosalind J Cutts, Hannah Bye, Matthew Beaney, Giselle Walsh-Crestani, Sarah Hrebien, Claire Swift, Lucy S Kilburn, Sarah Kernaghan, Laura Moretti, Katie Wilkinson, Andrew M Wardley, Iain R Macpherson, Richard D Baird, Rebecca Roylance, Jorge S Reis-Filho, Michael Hubank, Iris Faull, Kimberly C Banks, Richard B Lanman, Isaac Garcia-Murillas, Judith M Bliss, Alistair Ring, Nicholas C Turner.
      The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41467-021-22605-2
  8. BMC Cancer. 2021 Apr 19. 21(1): 429
    PTEN loss correlates with T cell exclusion across human cancers.
    Ziying Lin, Lixia Huang, Shao Li Li, Jincui Gu, Xiaoxian Cui, Yanbin Zhou.
       BACKGROUND: Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood.
    METHODS: Utilizing The Cancer Genome Atlas (TCGA) and publicly available dataset of immunotherapy, we explored the correlation of PTEN expressing level or genomic loss with tumor immune microenvironment and response to immunotherapy. We further investigated the involvement of PI3K-AKT-mTOR pathway activation, which is known to be the subsequent effect of PTEN loss, in the immune microenvironment modulation.
    RESULTS: We reveal that PTEN mRNA expression is significantly positively correlated with CD4/CD8A gene expression and T cells infiltration especially T helpers cells, central memory T cell and effector memory T cells in multiples tumor types. Genomic loss of PTEN is associated with reduced CD8+ T cells, type 1 T helper cells, and increased type 2 T helper cells, immunosuppressed genes (e.g. VEGFA) expression. Furthermore, T cell exclusive phenotype is also observed in tumor with PI3K pathway activation or genomic gain in PIK3CA or PIK3CB. PTEN loss and PI3K pathway activation correlate with immunosuppressive microenvironment, especially in terms of T cell exclusion. PTEN loss predict poor therapeutic response and worse survival outcome in patients receiving immunotherapy.
    CONCLUSION: These data brings insight into the role of PTEN loss in T cell exclusion and immunotherapy resistance, and inspires further research on immune modulating strategy to augment immunotherapy.
    Keywords:  Immunotherapy; PI3K signaling; PTEN; T cells; Tumor immune microenvironment
    DOI:  https://doi.org/10.1186/s12885-021-08114-x
  9. J Mol Cell Cardiol. 2021 Apr 19. pii: S0022-2828(21)00082-1. [Epub ahead of print]
    Pharmacological and cell-specific genetic PI3Kα inhibition worsens cardiac remodeling after myocardial infarction.
    Xueyi Chen, Pavel Zhabyeyev, Abul K Azad, Bart Vanhaesebroeck, Chad E Grueter, Allan G Murray, Zamaneh Kassiri, Gavin Y Oudit.
       BACKGROUND: PI3Kα (Phosphoinositide 3-kinase α) regulates multiple downstream signaling pathways controlling cell survival, growth, and proliferation and is an attractive therapeutic target in cancer and obesity. The clinically-approved PI3Kα inhibitor, BYL719, is in further clinical trials for cancer and overgrowth syndrome. However, the potential impact of PI3Kα inhibition on the heart and following myocardial infarction (MI) is unclear. We aim to determine whether PI3Kα inhibition affects cardiac physiology and post-MI remodeling and to elucidate the underlying molecular mechanisms.
    METHODS AND RESULTS: Wildtype (WT) 12-wk old male mice receiving BYL719 (daily, p.o.) for 10 days showed reduction in left ventricular longitudinal strain with normal ejection fraction, weight loss, mild cardiac atrophy, body composition alteration, and prolonged QTC interval. RNASeq analysis showed gene expression changes in multiple pathways including extracellular matrix remodeling and signaling complexes. After MI, both p110α and phospho-Akt protein levels were increased in human and mouse hearts. Pharmacological PI3Kα inhibition aggravated cardiac dysfunction and resulted in adverse post-MI remodeling, with increased apoptosis, elevated inflammation, suppressed hypertrophy, decreased coronary blood vessel density, and inhibited Akt/GSK3β/eNOS signaling. Selective genetic ablation of PI3Kα in endothelial cells was associated with worsened post-MI cardiac function and reduced coronary blood vessel density. In vitro, BYL719 suppressed Akt/eNOS activation, cell viability, proliferation, and angiogenic sprouting in coronary and human umbilical vein endothelial cells. Cardiomyocyte-specific genetic PI3Kα ablation resulted in mild cardiac systolic dysfunction at baseline. After MI, cardiac function markedly deteriorated with increased mortality concordant with greater apoptosis and reduced hypertrophy. In isolated adult mouse cardiomyocytes, BYL719 decreased hypoxia-associated activation of Akt/GSK3β signaling and cell survival.
    CONCLUSIONS: PI3Kα is required for cell survival (endothelial cells and cardiomyocytes) hypertrophic response, and angiogenesis to maintain cardiac function after MI. Therefore, PI3Kα inhibition that is used as anti-cancer treatment, can be cardiotoxic, especially after MI.
    Keywords:  Angiogenesis; Myocardial infarction; Myocardial remodeling; PI3Kα; Signaling
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.04.004
  10. J Clin Invest. 2021 Apr 20. pii: 143377. [Epub ahead of print]
    Glucose deprivation induced aberrant FUT1-mediated fucosylation drives cancer stemness in hepatocellular carcinoma.
    Jane Hc Loong, Tin-Lok Wong, Man Tong, Rakesh Sharma, Lei Zhou, Kai-Yu Ng, Hua-Jian Yu, Chi Han Li, Kwan Man, Chung-Mau Lo, Xin-Yuan Guan, Terence K Lee, Jing-Ping Yun, Stephanie Kwai Yee Ma.
      Rapidly growing tumors often experience hypoxia and nutrient (e.g., glucose) deficiency because of poor vascularization. Tumor cells respond to the cytotoxic effects of such stresses by inducing molecular adaptations that promote clonal selection of a more malignant tumor-initiating cell phenotype, especially in the innermost tumor regions. Here, we report a regulatory mechanism involving fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumor recurrence. Using hepatocellular carcinoma (HCC) as a model, we showed that restricted glucose availability enhanced the PERK-eIF2α-ATF4 signaling axis to drive fucosyltransferase-1 (FUT1) transcription via direct binding of ATF4 to the FUT1 promoter. FUT1 overexpression is a poor prognostic indicator for HCC. FUT1 inhibition could mitigate tumor initiation, self-renewal and drug resistance. Mechanistically, we demonstrated that CD147, ICAM-1, EGFR and EPHA2 are glycoprotein targets of FUT1, where such fucosylation would consequently converge on deregulated AKT-mTOR-4EBP1 signaling to drive cancer stemness. Treatment with an α-(1,2)-fucosylation inhibitor sensitized HCC tumors to sorafenib, a first-line molecular targeted drug used for advanced HCC patients, and reduced the tumor-initiating subset. FUT1 overexpression and/or CD147, ICAM-1, EGFR and EPHA2 fucosylation may be good prognostic markers and therapeutic targets for cancer patients.
    Keywords:  Cancer; Cell stress; Gastroenterology; Oncology; Signal transduction
    DOI:  https://doi.org/10.1172/JCI143377
  11. Nat Rev Clin Oncol. 2021 Apr 20.
    Copanlisib safe and active in combination.
    David Killock.
      
    DOI:  https://doi.org/10.1038/s41571-021-00512-1
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