bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2020‒11‒15
eleven papers selected by
Ralitsa Radostinova Madsen
University College London Cancer Institute

  1. Stem Cell Reports. 2020 Oct 30. pii: S2213-6711(20)30418-5. [Epub ahead of print]
      Insulin is an essential growth factor for the survival and self-renewal of human embryonic stem cells (hESCs). Although it is best known as the principal hormone promoting glycolysis in somatic cells, insulin's roles in hESC energy metabolism remain unclear. In this report, we demonstrate that insulin is essential to sustain hESC mitochondrial respiration that is rapidly decreased upon insulin removal. Insulin-dependent mitochondrial respiration is stem cell specific, and mainly relies on pyruvate and glutamine, while glucose suppresses excessive oxidative phosphorylation. Pharmacologic and genetic manipulations reveal that continuous insulin signal sustains mitochondrial respiration through PI3K/AKT activation and downstream GSK3 inhibition. We further show that insulin acts through GSK3 inhibition to suppress caspase activation and rescue cell survival. This study uncovers a critical role of the AKT/GSK3 pathway in the regulation of mitochondrial respiration and cell survival, highlighting insulin as an essential factor for accurate assessment of mitochondrial respiration in hESCs.
    Keywords:  AKT; GSK3; caspase; cell survival; human embryonic stem cells; insulin; mitochondrial respiration
  2. Blood Adv. 2020 Nov 10. 4(21): 5512-5526
      Hematopoietic stem cell (HSC) activity is tightly controlled to ensure the integrity of the hematopoietic system during the organism's lifetime. How the HSC compartment maintains its long-term fitness in conditions of chronic stresses associated with systemic metabolic disorders is poorly understood. In this study, we show that obesity functionally affects the long-term function of the most immature engrafting HSC subpopulation. We link this altered regenerative activity to the oxidative stress and the aberrant constitutive activation of the AKT signaling pathway that characterized the obese environment. In contrast, we found minor disruptions of the HSC function in obese mice at steady state, suggesting that active mechanisms could protect the HSC compartment from its disturbed environment. Consistent with this idea, we found that FOXO proteins in HSCs isolated from obese mice become insensitive to their normal upstream regulators such as AKT, even during intense oxidative stress. We established that hyperglycemia, a key condition associated with obesity, is directly responsible for the alteration of the AKT-FOXO axis in HSCs and their abnormal oxidative stress response. As a consequence, we observed that HSCs isolated from a hyperglycemic environment display enhanced resistance to oxidative stress and DNA damage. Altogether, these results indicate that chronic metabolic stresses associated with obesity and/or hyperglycemia affect the wiring of the HSCs and modify their oxidative stress response. These data suggest that the uncoupling of FOXO from its environmental regulators could be a key adaptive strategy that promotes the survival of the HSC compartment in obesity.
  3. Ann Oncol. 2020 Nov 10. pii: S0923-7534(20)43124-2. [Epub ahead of print]
      BACKGROUND: The phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer.PATIENTS AND METHODS: Postmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2:1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test), were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life.
    RESULTS: The PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib (7.4 months [95% CI, 7.26-9.07]) vs placebo arm (5.4 months [95% CI, 3.68-7.29]) (stratified HR 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo vs taselisib arm (8.9% vs 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm.
    CONCLUSION: SANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit.
    Keywords:  PI3K inhibitors; PIK3CA mutations; advanced breast cancer; taselisib
  4. PLoS One. 2020 ;15(11): e0241514
      Breast cancers with PIK3CA mutations can be treated with PIK3CA inhibitors in hormone receptor-positive HER2 negative subtypes. We applied a supervised elastic net penalized logistic regression model to predict PIK3CA mutations from gene expression data. This regression approach was applied to predict modeling using the TCGA pan-cancer dataset. Approximately 10,000 cases were available for PIK3CA mutation and mRNA expression data. In 10-fold cross-validation, the model with λ = 0.01 and α = 1.0 (ridge regression) showed the best performance, in terms of area under the receiver operating characteristic (AUROC). The final model was developed with selected hyper-parameters using the entire training set. The training set AUROC was 0.93, and the test set AUROC was 0.84. The area under the precision-recall (AUPR) of the training set was 0.66, and the test set AUPR was 0.39. Cancer types were the most important predictors. Both insulin like growth factor 1 receptor (IGF1R) and the phosphatase and tensin homolog (PTEN) were the most significant genes in gene expression predictors. Our study suggests that predicting genomic alterations using gene expression data is possible, with good outcomes.
  5. Surg Pathol Clin. 2020 Dec;pii: S1875-9181(20)30059-3. [Epub ahead of print]13(4): 719-728
      Vascular anomalies are composed of tumors and malformations and with overlapping histologies, thus are often misdiagnosed or labeled with imprecise terminology. Lesions are common and usually diagnosed during infancy or childhood; the estimated prevalence is 4.5%. Vascular tumors rapidly enlarge postnatally and demonstrate endothelial proliferation. Malformations are errors in vascular development with stable endothelial turnover; they are typically named based on the primary vessel that is malformed (capillary, arterial, venous, lymphatic). This article reviews the pathologic and molecular genetic characteristics for select recently described vascular anomalies.
    Keywords:  FAVA; Hemangioma; Lymphangiomatosis; Overgrowth; PROS; Vascular anomalies
  6. Cell Metab. 2020 Nov 06. pii: S1550-4131(20)30535-0. [Epub ahead of print]
      The emergence of cancer from diverse normal tissues has long been rationalized to represent a common set of fundamental processes. However, these processes are not fully defined. Here, we show that forced expression of glucose-6-phosphate dehydrogenase (G6PD) affords immortalized mouse and human cells anchorage-independent growth in vitro and tumorigenicity in animals. Mechanistically, G6PD augments the NADPH pool by stimulating NAD+ kinase-mediated NADP+ biosynthesis in addition to converting NADP+ to NADPH, bolstering antioxidant defense. G6PD also increases nucleotide precursor levels through the production of ribose and NADPH, promoting cell proliferation. Supplementation of antioxidants or nucleosides suffices to convert immortalized mouse and human cells into a tumorigenic state, and supplementation of both is required when their overlapping metabolic consequences are minimized. These results suggest that normal cells have a limited capacity for redox balance and nucleotide synthesis, and overcoming this limit might represent a key aspect of oncogenic transformation.
    Keywords:  G6PD; NAD kinase; NADPH; antioxidants; cancer metabolism; nucleosides; nucleotide synthesis; oncogenic transformation; pentose phosphate pathway; redox regulation
  7. Science. 2020 Nov 13. 370(6518): 853-856
      Shutoff of global protein synthesis is a conserved response to cellular stresses. This general phenomenon is accompanied by the induction of distinct gene programs tailored to each stress. Although the mechanisms driving repression of general protein synthesis are well characterized, how cells reprogram the translation machinery for selective gene expression remains poorly understood. Here, we found that the noncanonical 5' cap-binding protein eIF3d was activated in response to metabolic stress in human cells. Activation required reduced CK2-mediated phosphorylation near the eIF3d cap-binding pocket. eIF3d controls a gene program enriched in factors important for glucose homeostasis, including members of the mammalian target of rapamycin (mTOR) pathway. eIF3d-directed translation adaptation was essential for cell survival during chronic glucose deprivation. Thus, this mechanism of translation reprogramming regulates the cellular response to metabolic stress.
  8. Clin Cancer Res. 2020 Nov 09. pii: clincanres.3652.2020. [Epub ahead of print]
      On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.1 in the cohort of trial participants whose tumors had a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11.0 months (95% CI: 7.5, 14.5) compared with 5.7 months (95% CI: 3.7, 7.4) in the placebo plus fulvestrant arm (HR 0.65; 95% CI: 0.50, 0.85; two-sided p=0.001). The median overall survival (OS) was not yet reached for the alpelisib plus fulvestrant arm (95% CI: 28.1, NE) and was 26.9 months (95% CI: 21.9, NE) for the fulvestrant control arm. No PFS benefit was observed in trial participants whose tumors did not have a PIK3CA mutation (HR = 0.85; 95% CI: 0.58, 1.25).The most common adverse reactions, including laboratory abnormalities, on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia.
  9. Nat Commun. 2020 11 12. 11(1): 5726
      Apoptosis is an ancient and evolutionarily conserved cell suicide program. During apoptosis, executioner caspase enzyme activation has been considered a point of no return. However, emerging evidence suggests that some cells can survive caspase activation following exposure to apoptosis-inducing stresses, raising questions as to the physiological significance and underlying molecular mechanisms of this unexpected phenomenon. Here, we show that, following severe tissue injury, Drosophila wing disc cells that survive executioner caspase activation contribute to tissue regeneration. Through RNAi screening, we identify akt1 and a previously uncharacterized Drosophila gene CG8108, which is homologous to the human gene CIZ1, as essential for survival from the executioner caspase activation. We also show that cells expressing activated oncogenes experience apoptotic caspase activation, and that Akt1 and dCIZ1 are required for their survival and overgrowth. Thus, survival following executioner caspase activation is a normal tissue repair mechanism usurped to promote oncogene-driven overgrowth.
  10. Nucleic Acids Res. 2020 Nov 12. pii: gkaa1033. [Epub ahead of print]
      The prevalence of neutral mutations in cancer cell population impedes the distinguishing of cancer-causing driver mutations from passenger mutations. To systematically prioritize the oncogenic ability of somatic mutations and cancer genes, we constructed a useful platform, OncoVar (, which employed published bioinformatics algorithms and incorporated known driver events to identify driver mutations and driver genes. We identified 20 162 cancer driver mutations, 814 driver genes and 2360 pathogenic pathways with high-confidence by reanalyzing 10 769 exomes from 33 cancer types in The Cancer Genome Atlas (TCGA) and 1942 genomes from 18 cancer types in International Cancer Genome Consortium (ICGC). OncoVar provides four points of view, 'Mutation', 'Gene', 'Pathway' and 'Cancer', to help researchers to visualize the relationships between cancers and driver variants. Importantly, identification of actionable driver alterations provides promising druggable targets and repurposing opportunities of combinational therapies. OncoVar provides a user-friendly interface for browsing, searching and downloading somatic driver mutations, driver genes and pathogenic pathways in various cancer types. This platform will facilitate the identification of cancer drivers across individual cancer cohorts and helps to rank mutations or genes for better decision-making among clinical oncologists, cancer researchers and the broad scientific community interested in cancer precision medicine.
  11. Sci Signal. 2020 Nov 10. pii: eabb5727. [Epub ahead of print]13(657):
      The protein Dickkopf-1 (DKK1) is frequently overexpressed at the transcript level in hepatocellular carcinoma (HCC) and promotes metastatic progression through the induction of β-catenin, a Wnt signaling effector. We investigated how DKK1 expression is induced in HCC and found that activation of the epidermal growth factor receptor (EGFR) promoted parallel MEK-ERK and PI3K-Akt pathway signaling that converged to epigenetically stimulate DKK1 transcription. In HCC cell lines stimulated with EGF, EGFR-activated ERK phosphorylated the kinase PKM2 at Ser37, which promoted its nuclear translocation. Also in these cells, EGFR-activated Akt phosphorylated the acetyltransferase p300 at Ser1834 Subsequently, PKM2 and p300 mediated the phosphorylation and acetylation, respectively, of histone H3 at the DKK1 promoter, which synergistically enhanced DKK1 transcription. The mechanism was supported with mutational analyses in cells and in a chemically induced HCC model in rats. The findings suggest that dual inhibition of the MEK and PI3K pathways might suppress the expression of DKK1 and, consequently, tumor metastasis in patients with HCC.