bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2022‒06‒12
twenty-one papers selected by
Ralitsa Radostinova Madsen
University College London Cancer Institute
  1. Combination mTOR and SHP2 inhibitor treatment of lymphatic malformation endothelial cells.
  2. Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq.
  3. Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significant.
  4. The impact of PIK3R1 mutations and insulin-PI3K-glycolytic pathway regulation in prostate cancer.
  5. Vitamin B6 rescues insulin resistance and glucose-induced DNA damage caused by reduced activity of Drosophila PI3K.
  6. RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition.
  7. Proteomic alterations in extracellular vesicles induced by oncogenic PIK3CA mutations.
  8. High glutamine suppresses osteogenesis through mTORC1-mediated inhibition of the mTORC2/AKT-473/RUNX2 axis.
  9. RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells.
  10. MASTL is enriched in cancerous and pluripotent stem cells and influences OCT1/OCT4 levels.
  11. Progressive frontal intraosseous lipoma: Detection of the mosaic AKT1 variant discloses Proteus syndrome.
  12. Genomic characterization of lymphomas in patients with inborn errors of immunity.
  13. Thoracic venous malformation: a particular form of a visceral variant.
  14. Global-run on sequencing identifies Gm11967 as an Akt-dependent long noncoding RNA involved in insulin sensitivity.
  15. AKT constitutes a signal-promoted alternative exon-junction complex that regulates nonsense-mediated mRNA decay.
  16. Mutation and tissue lineage lead to organ-specific cancer.
  17. P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.
  18. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial.
  19. The polyol pathway is an evolutionarily conserved system for sensing glucose uptake.
  20. Mutations matter even if proteins stay the same.
  21. Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data.
  1. Microvasc Res. 2022 Jun 04. pii: S0026-2862(22)00087-5. [Epub ahead of print] 104397
    Combination mTOR and SHP2 inhibitor treatment of lymphatic malformation endothelial cells.
    Jennifer K Wolter, Ivette Valencia-Sama, Alex J Osborn, Evan J Propst, Meredith S Irwin, Blake Papsin, Nikolaus E Wolter.
      Mammalian target of rapamycin (mTOR) inhibitors are clinically effective at treating some complex lymphatic malformations (LM). The mTOR inhibitor rapamycin blocks the phosphoinositide 3-kinase (PI3K) pathway, which is commonly mutated in this condition. Although rapamycin is effective at controlling symptoms of LM, treatment courses are long, not all LMs respond to treatment, and many patients relapse after treatment has stopped. Concurrent rat sarcoma virus (RAS) pathway abnormalities have been identified in LM, which may limit the effectiveness of rapamycin. Protein tyrosine phosphatase-2 (SHP2) controls the RAS pathway upstream, and SHP2 inhibitors are being investigated for treatment of various tumors. The objective of this study was to determine the impact of SHP2 inhibition in combination with rapamycin on LM growth in vitro. Using primary patient cells isolated from a surgically resected LM, we found that combination treatment with rapamycin and the SHP2 inhibitor SHP099 caused a synergistic reduction in cell growth, migration and lymphangiogenesis. These results suggest that combination treatment targeting the PI3K and RAS signaling pathways may result in effective treatment of LMs of the head and neck.
    Keywords:  Lymphangiogenesis; Lymphatic malformation; PI3K; Rapamycin; SHP2
    DOI:  https://doi.org/10.1016/j.mvr.2022.104397
  2. Cell. 2022 Jun 02. pii: S0092-8674(22)00597-9. [Epub ahead of print]
    Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq.
    Joseph M Replogle, Reuben A Saunders, Angela N Pogson, Jeffrey A Hussmann, Alexander Lenail, Alina Guna, Lauren Mascibroda, Eric J Wagner, Karen Adelman, Gila Lithwick-Yanai, Nika Iremadze, Florian Oberstrass, Doron Lipson, Jessica L Bonnar, Marco Jost, Thomas M Norman, Jonathan S Weissman.
      A central goal of genetics is to define the relationships between genotypes and phenotypes. High-content phenotypic screens such as Perturb-seq (CRISPR-based screens with single-cell RNA-sequencing readouts) enable massively parallel functional genomic mapping but, to date, have been used at limited scales. Here, we perform genome-scale Perturb-seq targeting all expressed genes with CRISPR interference (CRISPRi) across >2.5 million human cells. We use transcriptional phenotypes to predict the function of poorly characterized genes, uncovering new regulators of ribosome biogenesis (including CCDC86, ZNF236, and SPATA5L1), transcription (C7orf26), and mitochondrial respiration (TMEM242). In addition to assigning gene function, single-cell transcriptional phenotypes allow for in-depth dissection of complex cellular phenomena-from RNA processing to differentiation. We leverage this ability to systematically identify genetic drivers and consequences of aneuploidy and to discover an unanticipated layer of stress-specific regulation of the mitochondrial genome. Our information-rich genotype-phenotype map reveals a multidimensional portrait of gene and cellular function.
    Keywords:  CRISPR; Integrator complex; Perturb-seq; cell biology; chromosomal instability; genetic screens; genotype-phenotype map; mitochondrial genome stress response; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.cell.2022.05.013
  3. NPJ Breast Cancer. 2022 Jun 08. 8(1): 71
    Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significant.
    Lizelle Correia, Ramiro Magno, Joana M Xavier, Bernardo P de Almeida, Isabel Duarte, Filipa Esteves, Marinella Ghezzo, Matthew Eldridge, Chong Sun, Astrid Bosma, Lorenza Mittempergher, Ana Marreiros, Rene Bernards, Carlos Caldas, Suet-Feung Chin, Ana-Teresa Maia.
      PIK3CA mutations are the most common in breast cancer, particularly in the estrogen receptor-positive cohort, but the benefit of PI3K inhibitors has had limited success compared with approaches targeting other less common mutations. We found a frequent allelic expression imbalance between the missense mutant and wild-type PIK3CA alleles in breast tumors from the METABRIC (70.2%) and the TCGA (60.1%) projects. When considering the mechanisms controlling allelic expression, 27.7% and 11.8% of tumors showed imbalance due to regulatory variants in cis, in the two studies respectively. Furthermore, preferential expression of the mutant allele due to cis-regulatory variation is associated with poor prognosis in the METABRIC tumors (P = 0.031). Interestingly, ER-, PR-, and HER2+ tumors showed significant preferential expression of the mutated allele in both datasets. Our work provides compelling evidence to support the clinical utility of PIK3CA allelic expression in breast cancer in identifying patients of poorer prognosis, and those with low expression of the mutated allele, who will unlikely benefit from PI3K inhibitors. Furthermore, our work proposes a model of differential regulation of a critical cancer-promoting gene in breast cancer.
    DOI:  https://doi.org/10.1038/s41523-022-00435-9
  4. Clin Cancer Res. 2022 Jun 07. pii: clincanres.4272.2021-12-1 23:41:01.777. [Epub ahead of print]
    The impact of PIK3R1 mutations and insulin-PI3K-glycolytic pathway regulation in prostate cancer.
    Goutam Chakraborty, Subhiksha Nandakumar, Rahim Hirani, Bastien Nguyen, Konrad H Stopsack, Christoph Kreitzer, Sai Harisha Rajanala, Romina Ghale, Ying Z Mazzu, Naga Vara Kishore Pillarsetty, Gwo-Shu Mary Lee, Howard I Scher, Michael J Morris, Tiffany Traina, Pedram Razavi, Wassim Abida, Jeremy C Durack, Stephen B Solomon, Matthew G Vander Heiden, Lorelei A Mucci, Andreas G Wibmer, Nikolaus Schultz, Philip W Kantoff.
      PURPOSE: Oncogenic alterations of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway occur in >40% of patients with metastatic castration-resistant prostate cancer (mCRPC), predominantly via PTEN loss. The significance of other PI3K pathway components in prostate cancer is largely unknown.EXPERIMENTAL DESIGN: Patients in this study underwent tumor sequencing using the MSK-IMPACT clinical assay to capture single-nucleotide variants, insertions, and deletions, copy number alterations, and structural rearrangements, or were profiled through The Cancer Genome Atlas. The association between PIK3R1 alteration/expression and survival was evaluated using univariable and multivariable Cox proportional-hazards regression models. We used siRNA-based knockdown of PIK3R1 for functional studies. FDG-PET/CT examinations were performed with a hybrid PET/CT scanner for some prostate cancer patients in MSK-IMPACT cohort.
    RESULTS: Analyzing 1417 human prostate cancers, we found a significant enrichment of PIK3R1 alterations in metastatic cancers compared to primary cancers. PIK3R1 alterations or reduced mRNA expression tended to be associated with worse clinical outcomes in prostate cancer, particularly in primary disease, as well as in breast, gastric, and several other cancers. In prostate cancer cell lines, PIK3R1 knockdown resulted in increased cell proliferation and AKT activity, including insulin-stimulated AKT activity. In cell lines and organoids, PIK3R1 loss/mutation was associated with increased sensitivity to AKT inhibitors. PIK3R1-altered patient prostate tumors had increased uptake of the glucose analogue 18F-fluorodeoxyglucose in PET imaging, suggesting increased glycolysis.
    CONCLUSIONS: Our findings describe a novel genomic feature in metastatic prostate cancer and suggest that PIK3R1 alteration may be a key event for insulin-PI3K-glycolytic pathway regulation in prostate cancer.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-4272
  5. J Cell Physiol. 2022 Jun 09.
    Vitamin B6 rescues insulin resistance and glucose-induced DNA damage caused by reduced activity of Drosophila PI3K.
    Elisa Mascolo, Francesco Liguori, Chiara Merigliano, Ludovica Schiano, Eleonora Gnocchini, Eleonora Pilesi, Cinzia Volonté, Martino L Di Salvo, Roberto Contestabile, Angela Tramonti, Fiammetta Vernì.
      The insulin signaling pathway controls cell growth and metabolism, thus its deregulation is associated with both cancer and diabetes. Phosphatidylinositol 3-kinase (PI3K) contributes to the cascade of phosphorylation events occurring in the insulin pathway by activating the protein kinase B (PKB/AKT), which phosphorylates several substrates, including those involved in glucose uptake and storage. PI3K inactivating mutations are associated with insulin resistance while activating mutations are identified in human cancers. Here we show that RNAi-induced depletion of the Drosophila PI3K catalytic subunit (Dp110) results in diabetic phenotypes such as hyperglycemia, body size reduction, and decreased glycogen content. Interestingly, we found that hyperglycemia produces chromosome aberrations (CABs) triggered by the accumulation of advanced glycation end-products and reactive oxygen species. Rearing PI3KRNAi flies in a medium supplemented with pyridoxal 5'-phosphate (PLP; the catalytically active form of vitamin B6) rescues DNA damage while, in contrast, treating PI3KRNAi larvae with the PLP inhibitor 4-deoxypyridoxine strongly enhances CAB frequency. Interestingly, PLP supplementation rescues also diabetic phenotypes. Taken together, our results provide a strong link between impaired PI3K activity and genomic instability, a crucial relationship that needs to be monitored not only in diabetes due to impaired insulin signaling but also in cancer therapies based on PI3K inhibitors. In addition, our findings confirm the notion that vitamin B6 is a good natural remedy to counteract insulin resistance and its complications.
    Keywords:  DNA damage; Drosophila; insulin signaling; phosphatidylinositol 3-Kinase; pyridoxal phosphate
    DOI:  https://doi.org/10.1002/jcp.30812
  6. Nat Commun. 2022 Jun 08. 13(1): 3181
    RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition.
    Lishan Fang, Dane Ford-Roshon, Max Russo, Casey O'Brien, Xiaozhe Xiong, Carino Gurjao, Maximilien Grandclaudon, Srivatsan Raghavan, Steven M Corsello, Steven A Carr, Namrata D Udeshi, James Berstler, Ewa Sicinska, Kimmie Ng, Marios Giannakis.
      The RNF43_p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43_p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43_p.G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43659mut isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43659mut may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers.
    DOI:  https://doi.org/10.1038/s41467-022-30794-7
  7. Proteomics. 2022 Jun 11. e2200077
    Proteomic alterations in extracellular vesicles induced by oncogenic PIK3CA mutations.
    Mayank Saraswat, Kishore Garapati, Jinyong Kim, Rohit Budhraja, Akhilesh Pandey.
      PIK3CA is one of the most frequently mutated genes in human cancers, with the two most prevalent activating mutations being E545K and H1047R. Although the altered intracellular signaling pathways in these cells have been described, the effect of these mutations on their extracellular vesicles (EVs) has not yet been reported. To study altered cellular physiology and intercellular communication through proteomic analysis of EVs, MCF10A cells and their isogenic mutant versions (PIK3CA E545K and H1047R) were cultured and their EVs enriched by differential ultracentrifugation. Proteins were extracted, digested with trypsin and the peptides labeled with tandem mass tag (TMT) reagents and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). 4,655 peptides were identified from 579 proteins of which 522 proteins have been previously described in EVs. Relative quantitation revealed altered levels of EV proteins including several cell adhesion molecules. Mesothelin, E-cadherin and epithelial cell adhesion molecule were elevated in both mutant cell-derived EVs. Markers of tumor invasion and progression like galectin-3 and transforming growth factor beta induced protein were increased in both mutants. Overall, activating mutations in PIK3CA result in altered EV composition with characteristic changes associated with these hotspot mutations. This article is protected by copyright. All rights reserved.
    Keywords:  PI3K; exosomes; mass spectrometry; oncogenic mutation; proteomics
    DOI:  https://doi.org/10.1002/pmic.202200077
  8. Cell Death Discov. 2022 Jun 07. 8(1): 277
    High glutamine suppresses osteogenesis through mTORC1-mediated inhibition of the mTORC2/AKT-473/RUNX2 axis.
    Meher Bolisetti Gayatri, Navya Naidu Gajula, Suresh Chava, Aramati B M Reddy.
      Activation of the key nutrient cellular sensors mTORC1 and mTORC2 directs the fate of mesenchymal stromal cells (MSCs). Here, we report that glutamine regulates crosstalk between mTOR complexes and lineage commitment of MSCs independent of glucose concentration. High glutamine-induced mTORC1 hyperactivation resulted in the suppression of mTORC2, which otherwise stabilizes RUNX2 via GSK3β inhibition through pAKT-473. Activation of GSK3β resulted in the ubiquitination of RUNX2, a key transcription factor for the osteogenic commitment of MSCs. However, low glutamine conditions inhibit mTORC1 hyperactivation followed by increased mTORC2 activation and RUNX2 stabilization. Under diabetic/high-glucose conditions, glutamine-triggered hyperactivation of mTORC1 resulted in mTORC2 suppression, and active GSK3β led to suppression of RUNX2. Activation of p-AMPK by metformin inhibits high glutamine-induced mTORC1 hyperactivation and rescues RUNX2 through the mTORC2/AKT-473 axis. Collectively, our study indicates the role of glutamine in modulating MSC fate through cross-talk between mTOR complexes by identifying a critical switch in signaling. It also shows the importance of glutamine in modulating molecular cues (mTORC1/p-70S6K/mTORC2/RUNX2) that are involved in driving diabetes-induced bone adipogenesis and other secondary complications.
    DOI:  https://doi.org/10.1038/s41420-022-01077-3
  9. Theranostics. 2022 ;12(9): 4348-4373
    RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells.
    Lena Hölzen, Jan Mitschke, Claudia Schönichen, Maria Elena Hess, Sophia Ehrenfeld, Melanie Boerries, Cornelius Miething, Tilman Brummer, Thomas Reinheckel.
      RATIONALE: PI3K/mTOR signaling is frequently upregulated in breast cancer making inhibitors of this pathway highly promising anticancer drugs. However, PI3K-inhibitors have a low therapeutic index. Therefore, finding novel combinatory treatment options represents an important step towards clinical implementation of PI3K pathway inhibition in breast cancer therapy. Here, we propose proteases as potential synergistic partners with simultaneous PI3K inhibition in breast cancer cells.METHODS: We performed mRNA expression studies and unbiased functional genetic synthetic lethality screens by a miR-E based knockdown system targeting all genome-encoded proteases, i.e. the degradome of breast cancer cells. Importantly theses RNA interference screens were done in combination with two PI3K pathway inhibitors. Protease hits were validated in human and murine breast cancer cell lines as well as in non-cancerous cells by viability and growth assays.
    RESULTS: The degradome-wide genetic screens identified 181 proteases that influenced susceptibility of murine breast cancer cells to low dose PI3K inhibition. Employing independently generated inducible knockdown cell lines we validated 12 protease hits in breast cancer cells. In line with the known tumor promoting function of these proteases we demonstrated Usp7 and Metap2 to be important for murine and human breast cancer cell growth and discovered a role for Metap1 in this context. Most importantly, we demonstrated that Usp7, Metap1 or Metap2 knockdown combined with simultaneous PI3K inhibition resulted in synergistic impairment of murine and human breast cancer cell growth Conclusion: We successfully established proteases as combinatory targets with PI3K inhibition in human and murine breast cancer cells. Usp7, Metap1 and Metap2 are synthetic lethal partners of simultaneous protease/PI3K inhibition, which may refine future breast cancer therapy.
    Keywords:  Breast Cancer; Cancer Degradome; Phosphatidylinositol-3-kinase (PI3K)-Pathway; Proteases; RNA Interference
    DOI:  https://doi.org/10.7150/thno.68299
  10. iScience. 2022 Jun 17. 25(6): 104459
    MASTL is enriched in cancerous and pluripotent stem cells and influences OCT1/OCT4 levels.
    Elisa Närvä, Maria E Taskinen, Sergio Lilla, Aleksi Isomursu, Mika Pietilä, Jere Weltner, Jorma Isola, Harri Sihto, Heikki Joensuu, Sara Zanivan, Jim Norman, Johanna Ivaska.
      MASTL is a mitotic accelerator with an emerging role in breast cancer progression. However, the mechanisms behind its oncogenicity remain largely unknown. Here, we identify a previously unknown role and eminent expression of MASTL in stem cells. MASTL staining from a large breast cancer patient cohort indicated a significant association with β3 integrin, an established mediator of breast cancer stemness. MASTL silencing reduced OCT4 levels in human pluripotent stem cells and OCT1 in breast cancer cells. Analysis of the cell-surface proteome indicated a strong link between MASTL and the regulation of TGF-β receptor II (TGFBR2), a key modulator of TGF-β signaling. Overexpression of wild-type and kinase-dead MASTL in normal mammary epithelial cells elevated TGFBR2 levels. Conversely, MASTL depletion in breast cancer cells attenuated TGFBR2 levels and downstream signaling through SMAD3 and AKT pathways. Taken together, these results indicate that MASTL supports stemness regulators in pluripotent and cancerous stem cells.
    Keywords:  Cancer; Cell biology; Proteomics; Stem cells research
    DOI:  https://doi.org/10.1016/j.isci.2022.104459
  11. Clin Genet. 2022 Jun 07.
    Progressive frontal intraosseous lipoma: Detection of the mosaic AKT1 variant discloses Proteus syndrome.
    Julia Schmidt, Felix Bremmer, Knut Brockmann, Silke Kaulfuß, Bernd Wollnik.
      Proteus syndrome is a very rare disorder with progressive, asymmetrical and disproportionate overgrowth of body parts with a highly variable phenotype. It is associated with mosaicism for the recurrent heterozygous somatic gain-of-function variant c.49G>A (p.Glu17Lys) in the protein kinase AKT1. We report on a girl with a progressive intraosseous lipoma of the frontal bone and additional, non-specific features including mild developmental delay, strabism, and a limbal dermoid of the left eye. She did not fulfill the criteria for a clinical diagnosis of Proteus syndrome. However, mutation analysis of AKT1 in a lipoma biopsy revealed this specific activating variant. Several cases of progressive intraosseous lipoma of the frontal bone have been reported in the literature. Only in two of these observations a tentative diagnosis of Proteus syndrome was made, based on additional clinical features, although without molecular-genetic verification. We conclude that oligosymptomatic Proteus syndrome should be considered in progressive intraosseous lipoma, as recognition of this diagnosis has relevant implications for genetic counselling and opens novel treatment options with AKT1 inhibitors rather than surgical procedures.
    Keywords:  AKT1; Proteus syndrome; frontal intraosseous lipoma; malformation syndrome; mosaic disorders
    DOI:  https://doi.org/10.1111/cge.14174
  12. Blood Adv. 2022 Jun 10. pii: bloodadvances.2021006654. [Epub ahead of print]
    Genomic characterization of lymphomas in patients with inborn errors of immunity.
    Xiaofei Ye, Paul J Maglione, Claudia Wehr, Xiaobo Li, Yating Wang, Hassan Abolhassani, Elena Deripapa, Dongbing Liu, Stephan Borte, Likun Du, Hui Wan, Andreas Plötner, Yvonne Giannoula, Huaibin Mabel Ko, Yong Hou, Shida Zhu, Jennifer K Grossman, Birgitta Sander, Bodo Grimbacher, Lennart Hammarström, Alina Fedorova, Sergio Rosenzweig, Anna Shcherbina, Kui Wu, Klaus Warnatz, Charlotte Cunningham-Rundles, Qiang Pan-Hammarström.
      Patients with inborn errors of immunity (IEI) have a higher risk of developing cancer, especially lymphoma. However, the molecular basis for IEI-related lymphoma is complex and remains elusive. Here, we perform an in-depth analysis of lymphoma genomes derived from 23 IEI patients. We identified and validated disease-causing or associated germline mutations in 14 of 23 patients involving ATM, BACH2, BLM, CD70, G6PD, NBN, PIK3CD, PTEN, and TNFRSF13B. Furthermore, we profiled somatic mutations in the lymphoma genome and identified eight genes that were mutated at a significantly higher level in IEI-associated diffuse large B-cell lymphomas (DLBCLs) than in non-IEI DLBCLs, such as BRCA2, NCOR1, KLF2, FAS, CCND3, and BRWD3. The latter, BRWD3, is furthermore preferentially mutated in tumors of a subgroup of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome patients. We also identified five genomic mutational signatures, including two DNA repair deficiency-related signatures, in IEI-associated lymphomas and a strikingly high number of inter- and intrachromosomal structural variants in the tumor genome of a Bloom syndrome patient. In summary, our comprehensive genomic characterization of lymphomas derived from patients with rare genetic disorders expands our understanding of lymphomagenesis and provides new insights for targeted therapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2021006654
  13. BMJ Case Rep. 2022 Jun 10. pii: e250307. [Epub ahead of print]15(6):
    Thoracic venous malformation: a particular form of a visceral variant.
    Inês Pessanha, Paloma Triana, Victor Martinez-Glez, Juan Carlos Lopez-Gutierrez.
      A teenage boy was admitted due to a thoracic mass with previous respiratory infections. The CT scan showed phleboliths in a cystic lesion with large draining channels. He also presented a mild thrombocytosis, elevated fibrinogen and D-dimer. Arteriogram revealed no abnormal arterial supply but venography proved venous draining channels as the major components of the lesion. The most important venous pedicle was embolised. However, 6 months later, CT scan showed no reduction in lesion size. Surgical resection was performed. Anatomopathological study described a venous malformation (VM) with a lymphatic component, and genetic testing found a typical mutation in PIK3CA and genetic variant in MAP3K3 This case reports a very rare pattern of thoracic vascular tumour. The authors aim to highlight the importance of genetic studies of VM with atypical presentation in order to achieve a definitive diagnosis.
    Keywords:  Genetics; Interventional radiology; Paediatric Surgery; Paediatrics; Pathology
    DOI:  https://doi.org/10.1136/bcr-2022-250307
  14. iScience. 2022 Jun 17. 25(6): 104410
    Global-run on sequencing identifies Gm11967 as an Akt-dependent long noncoding RNA involved in insulin sensitivity.
    Dominic Santoleri, Hee-Woong Lim, Matthew J Emmett, Julian Stoute, Matthew J Gavin, Jaimarie Sostre-Colón, Kahealani Uehara, Jaclyn E Welles, Kathy Fange Liu, Mitchell A Lazar, Paul M Titchenell.
      The insulin responsive Akt and FoxO1 signaling axis is a key regulator of the hepatic transcriptional response to nutrient intake. Here, we used global run-on sequencing (GRO-seq) to measure the nascent transcriptional response to fasting and refeeding as well as define the specific role of hepatic Akt and FoxO1 signaling in mediating this response. We identified 599 feeding-regulated transcripts, as well as over 6,000 eRNAs, and mapped their dependency on Akt and FoxO1 signaling. Further, we identified several feeding-regulated lncRNAs, including the lncRNA Gm11967, whose expression was dependent upon the liver Akt-FoxO1 axis. Restoring Gm11967 expression in mice lacking liver Akt improved insulin sensitivity and induced glucokinase protein expression, indicating that Akt-dependent control of Gm11967 contributes to the translational control of glucokinase. More broadly, we have generated a unique genome-wide dataset that defines the feeding and Akt/FoxO1-dependent transcriptional changes in response to nutrient availability.
    Keywords:  Molecular Physiology; Omics; Physiology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2022.104410
  15. Mol Cell. 2022 Jun 03. pii: S1097-2765(22)00480-4. [Epub ahead of print]
    AKT constitutes a signal-promoted alternative exon-junction complex that regulates nonsense-mediated mRNA decay.
    Hana Cho, Elizabeth T Abshire, Maximilian W Popp, Christoph Pröschel, Joshua L Schwartz, Gene W Yeo, Lynne E Maquat.
      Despite a long appreciation for the role of nonsense-mediated mRNA decay (NMD) in destroying faulty, disease-causing mRNAs and maintaining normal, physiologic mRNA abundance, additional effectors that regulate NMD activity in mammalian cells continue to be identified. Here, we describe a haploid-cell genetic screen for NMD effectors that has unexpectedly identified 13 proteins constituting the AKT signaling pathway. We show that AKT supersedes UPF2 in exon-junction complexes (EJCs) that are devoid of RNPS1 but contain CASC3, defining an unanticipated insulin-stimulated EJC. Without altering UPF1 RNA binding or ATPase activity, AKT-mediated phosphorylation of the UPF1 CH domain at T151 augments UPF1 helicase activity, which is critical for NMD and also decreases the dependence of helicase activity on ATP. We demonstrate that upregulation of AKT signaling contributes to the hyperactivation of NMD that typifies Fragile X syndrome, as exemplified using FMR1-KO neural stem cells derived from induced pluripotent stem cells.
    Keywords:  AKT signaling; Fragile X syndrome; UPF1 helicase and RNA-binding activities; UPF1 phosphorylation; afuresertib; alternative exon-junction complexes; human haploid-cell screen; insulin; nonsense-mediated mRNA decay
    DOI:  https://doi.org/10.1016/j.molcel.2022.05.013
  16. Nature. 2022 Jun 08.
    Mutation and tissue lineage lead to organ-specific cancer.
    Emily N Arner, W Kimryn Rathmell.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-022-01535-z
  17. Nat Cancer. 2022 Jun 06.
    P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.
    Kevin H Lin, Justine C Rutter, Abigail Xie, Shane T Killarney, Camille Vaganay, Chaima Benaksas, Frank Ling, Gaetano Sodaro, Paul-Arthur Meslin, Christopher F Bassil, Nina Fenouille, Jacob Hoj, Rachel Washart, Hazel X Ang, Christian Cerda-Smith, Paul Chaintreuil, Arnaud Jacquel, Patrick Auberger, Antoine Forget, Raphael Itzykson, Min Lu, Jiaxing Lin, Mariaelena Pierobon, Zhecheng Sheng, Xinghai Li, Ashutosh Chilkoti, Kouros Owzar, David A Rizzieri, Timothy S Pardee, Lina Benajiba, Emanuel Petricoin, Alexandre Puissant, Kris C Wood.
      Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment. We discover that selinexor activates PI3Kγ-dependent AKT signaling in AML by upregulating the purinergic receptor P2RY2. Inhibiting this axis potentiates the anti-leukemic effects of selinexor in AML cell lines, patient-derived primary cultures and multiple mouse models of AML. In a syngeneic, MLL-AF9-driven mouse model of AML, treatment with selinexor and ipatasertib outperforms both standard-of-care chemotherapy and chemotherapy with selinexor. Together, these findings establish drug-induced P2RY2-AKT signaling as an actionable consequence of XPO1 inhibition in AML.
    DOI:  https://doi.org/10.1038/s43018-022-00394-x
  18. Lancet Oncol. 2022 Jun 01. pii: S1470-2045(22)00284-4. [Epub ahead of print]
    Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial.
    Sacha J Howell, Angela Casbard, Margherita Carucci, Kate Ingarfield, Rachel Butler, Sian Morgan, Magdalena Meissner, Catherine Bale, Pavel Bezecny, Sarah Moon, Chris Twelves, Ramachandran Venkitaraman, Simon Waters, Elza C de Bruin, Gaia Schiavon, Andrew Foxley, Robert H Jones.
      BACKGROUND: Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The benefit appeared to be independent of the phosphoinositide 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) pathway alteration status of tumours, as ascertained using assays available at the time. Here, we report updated progression-free survival and overall survival results, and a prespecified examination of the effect of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel on treatment outcomes.METHODS: This randomised, multicentre, double-blind, placebo-controlled, phase 2 trial recruited postmenopausal adult women aged at least 18 years with ER-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2, who had relapsed or progressed on an aromatase inhibitor, from across 19 hospitals in the UK. Participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a 500 mg loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on cycle 1 day 15. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment was allocated by an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival in the intention-to-treat population. Secondary endpoints shown in this Article were overall survival and safety in the intention-to-treat population, and the effect of tumour PI3K/AKT/PTEN pathway status identified by an expanded testing panel that included next-generation sequencing assays. Recruitment is complete. The trial is registered with ClinicalTrials.gov, number NCT01992952.
    FINDINGS: Between March 16, 2015, and March 6, 2018, 183 participants were screened for eligibility and 140 (77%) were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up at the data cut-off of Nov 25, 2021, was 58·5 months (IQR 45·9-64·1) for participants treated with fulvestrant plus capivasertib and 62·3 months (IQR 62·1-70·3) for fulvestrant plus placebo. Updated median progression-free survival was 10·3 months (95% CI 5·0-13·4) in the group receiving fulvestrant plus capivasertib compared with 4·8 months (3·1-7·9) for fulvestrant plus placebo (adjusted hazard ratio [HR] 0·56 [95% CI 0·38-0·81]; two-sided p=0·0023). Median overall survival in the capivasertib versus placebo groups was 29·3 months (95% CI 23·7-39·0) versus 23·4 months (18·7-32·7; adjusted HR 0·66 [95% CI 0·45-0·97]; two-sided p=0·035). The expanded biomarker panel identified an expanded pathway-altered subgroup that contained 76 participants (54% of the intention-to-treat population). Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12·8 months (95% CI 6·6-18·8) compared with 4·6 months (2·8-7·9) in the placebo group (n=37; adjusted HR 0·44 [95% CI 0·26-0·72]; two-sided p=0·0014). Median overall survival for the expanded pathway-altered subgroup receiving capivasertib was 38·9 months (95% CI 23·3-50·7) compared with 20·0 months (14·8-31·4) for those receiving placebo (adjusted HR 0·46 [95% CI 0·27-0·79]; two-sided p=0·0047). By contrast, there were no statistically significant differences in progression-free or overall survival in the expanded pathway non-altered subgroup treated with capivasertib (n=30) versus placebo (n=34). One additional serious adverse event (pneumonia) in the capivasertib group had occurred subsequent to the primary analysis. One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment.
    INTERPRETATION: Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumours. Phase 3 data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial.
    FUNDING: AstraZeneca and Cancer Research UK.
    DOI:  https://doi.org/10.1016/S1470-2045(22)00284-4
  19. PLoS Biol. 2022 Jun 10. 20(6): e3001678
    The polyol pathway is an evolutionarily conserved system for sensing glucose uptake.
    Hiroko Sano, Akira Nakamura, Mariko Yamane, Hitoshi Niwa, Takashi Nishimura, Kimi Araki, Kazumasa Takemoto, Kei-Ichiro Ishiguro, Hiroki Aoki, Yuzuru Kato, Masayasu Kojima.
      Cells must adjust the expression levels of metabolic enzymes in response to fluctuating nutrient supply. For glucose, such metabolic remodeling is highly dependent on a master transcription factor ChREBP/MondoA. However, it remains elusive how glucose fluctuations are sensed by ChREBP/MondoA despite the stability of major glycolytic pathways. Here, we show that in both flies and mice, ChREBP/MondoA activation in response to glucose ingestion involves an evolutionarily conserved glucose-metabolizing pathway: the polyol pathway. The polyol pathway converts glucose to fructose via sorbitol. It has been believed that this pathway is almost silent, and its activation in hyperglycemic conditions has deleterious effects on human health. We show that the polyol pathway regulates the glucose-responsive nuclear translocation of Mondo, a Drosophila homologue of ChREBP/MondoA, which directs gene expression for organismal growth and metabolism. Likewise, inhibition of the polyol pathway in mice impairs ChREBP's nuclear localization and reduces glucose tolerance. We propose that the polyol pathway is an evolutionarily conserved sensing system for glucose uptake that allows metabolic remodeling.
    DOI:  https://doi.org/10.1371/journal.pbio.3001678
  20. Nature. 2022 Jun 08.
    Mutations matter even if proteins stay the same.
    Nathaniel Sharp.
      
    Keywords:  Evolution; Genetics
    DOI:  https://doi.org/10.1038/d41586-022-01091-6
  21. Nat Commun. 2022 Jun 09. 13(1): 3224
    Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data.
    Daniel Dimitrov, Dénes Türei, Martin Garrido-Rodriguez, Paul L Burmedi, James S Nagai, Charlotte Boys, Ricardo O Ramirez Flores, Hyojin Kim, Bence Szalai, Ivan G Costa, Alberto Valdeolivas, Aurélien Dugourd, Julio Saez-Rodriguez.
      The growing availability of single-cell data, especially transcriptomics, has sparked an increased interest in the inference of cell-cell communication. Many computational tools were developed for this purpose. Each of them consists of a resource of intercellular interactions prior knowledge and a method to predict potential cell-cell communication events. Yet the impact of the choice of resource and method on the resulting predictions is largely unknown. To shed light on this, we systematically compare 16 cell-cell communication inference resources and 7 methods, plus the consensus between the methods' predictions. Among the resources, we find few unique interactions, a varying degree of overlap, and an uneven coverage of specific pathways and tissue-enriched proteins. We then examine all possible combinations of methods and resources and show that both strongly influence the predicted intercellular interactions. Finally, we assess the agreement of cell-cell communication methods with spatial colocalisation, cytokine activities, and receptor protein abundance and find that predictions are generally coherent with those data modalities. To facilitate the use of the methods and resources described in this work, we provide LIANA, a LIgand-receptor ANalysis frAmework as an open-source interface to all the resources and methods.
    DOI:  https://doi.org/10.1038/s41467-022-30755-0
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