bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2021–07–04
twelve papers selected by
Ralitsa Radostinova Madsen, University College London
  1. PIK3CA-related overgrowth spectrum: animal model and drug discovery.
  2. AKT1 and PTEN show the highest affinities among phosphoinositide binding proteins for the second messengers PtdIns(3,4,5)P3 and PtdIns(3,4)P2.
  3. Vascular Effects of Disrupting Endothelial mTORC1 (Mechanistic Target of Rapamycin Complex 1) Signaling in Obesity.
  4. Lacrimal gland budding requires PI3K-dependent suppression of EGF signaling.
  5. The Evolving Use of Phosphatidylinositol 3-Kinase Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.
  6. Inhibition of RPS6K reveals context-dependent Akt activity in luminal breast cancer cells.
  7. Feedback, Crosstalk and Competition: Ingredients for Emergent Non-Linear Behaviour in the PI3K/mTOR Signalling Network.
  8. Cell Biology of Canonical Wnt Signaling.
  9. PTEN Hamartoma Tumor Syndrome/Cowden Syndrome: Genomics, Oncogenesis, and Imaging Review for Associated Lesions and Malignancy.
  10. Embryo-scale, single-cell spatial transcriptomics.
  11. NF-κB responds to absolute differences in cytokine concentrations.
  12. p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino.
  1. C R Biol. 2021 Jul 02. 344(2): 189-201
    PIK3CA-related overgrowth spectrum: animal model and drug discovery.
    Quitterie Venot, Guillaume Canaud.
      This review recapitulates the recent knowledge accumulation on overgrowth syndrome related to gain of function of the phosphoinositide3 kinase (PI3K)-alpha. These disorders, known as PIK3CA related overgrowth syndromes (PROS) are caused by somatic PIK3CA mutation occurring during embryogenesis. We summarize here the currently available animal models and new treatments undergoing development.
    Keywords:  Animal model; Clinical trial; Mosaicism; PIK3CA; PIK3CA-related overgrowth spectrum
    DOI:  https://doi.org/10.5802/crbiol.50
  2. Biochem Biophys Res Commun. 2021 Jun 29. pii: S0006-291X(21)00948-7. [Epub ahead of print]568 110-115
    AKT1 and PTEN show the highest affinities among phosphoinositide binding proteins for the second messengers PtdIns(3,4,5)P3 and PtdIns(3,4)P2.
    Nina Nelson, Adelia Razeto, Alessia Gilardi, Mira Grättinger, Johannes Kirchmair, Manfred Jücker.
      The phosphoinositides phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3] and phosphatidylinositol-3,4-bisphosphate [PtdIns(3,4)P2] function as second messengers and have been implicated in cancerogenesis. The signalling events downstream of PtdIns(3,4,5)P3 and PtdIns(3,4)P2 are mediated through a complex network of phosphoinositide binding effector proteins and phosphatases. In this study, we compared the phosphoinositide effector proteins AKT1, TAPP1, TAPP2, VAV1 and P-REX1 and the phosphoinositide phosphatases PTEN, SHIP1 and INPP4B for their binding affinities to PtdIns(3,4,5)P3 and/or PtdIns(3,4)P2 using Surface Plasmon Resonance. Our results demonstrate that all measured proteins except P-REX1 and VAV1 showed high affinity phosphoinositide binding with KD values in the nM to sub-nM range. Within the effector proteins, AKT1 showed the highest affinity for both PtdIns(3,4,5)P3 and PtdIns(3,4)P2. Of the phosphoinositide phosphatases PTEN displayed the highest affinity towards PtdIns(3,4,5)P3 and PtdIns(3,4)P2. The SHIP1 mutant E452K detected in carcinoma patients had a 100-fold increased affinity to PtdIns(3,4)P2 but not to PtdIns(3,4,5)P3 compared to SHIP1 WT. Distinct mutations in phosphoinositide binding proteins like the patient-derived SHIP1E452K mutant may be involved in the upregulation of PI(3,4)P2 -mediated signalling in tumor cells due to phosphoinositide trapping. Our results add further information to the complex hierarchy of phosphoinositide binding proteins helping to elucidate their functional role in cellular signal transduction.
    Keywords:  Phosphatidylinositol-3,4,5-trisphosphate; Phosphatidylinositol-3,4-bisphosphate; Second messenger; Surface plasmon resonance
    DOI:  https://doi.org/10.1016/j.bbrc.2021.06.027
  3. Am J Physiol Regul Integr Comp Physiol. 2021 06 30.
    Vascular Effects of Disrupting Endothelial mTORC1 (Mechanistic Target of Rapamycin Complex 1) Signaling in Obesity.
    John J Reho, Deng-Fu Guo, Andreas M Beyer, Lauren Wegman-Points, Gary L Pierce, Kamal Rahmouni.
      The mechanistic target of rapamycin complex 1 (mTORC1) signaling complex is emerging as a critical regulator of cardiovascular function with alterations in this pathway implicated in cardiovascular diseases. In this study, we utilized animal models and human tissues to examine the role of vascular mTORC1 signaling in the endothelial dysfunction associated with obesity. In mice, obesity induced by high fat/high sucrose diet feeding for ~2 months resulted in aortic endothelial dysfunction without appreciable changes in vascular mTORC1 signaling. On the other hand, chronic high fat diet feeding (45% or 60% kcal: ~9 months) in mice resulted in endothelial dysfunction associated with elevated vascular mTORC1 signaling. Endothelial cells and visceral adipose vessels isolated from obese humans display a trend toward elevated mTORC1 signaling. Surprisingly, genetic disruption of endothelial mTORC1 signaling through constitutive or tamoxifen inducible deletion of endothelial Raptor (critical subunit of mTORC1) did not prevent or rescue the endothelial dysfunction associated with high fat diet feeding in mice. Endothelial mTORC1 deficiency also failed to reverse the endothelial dysfunction evoked by a high fat/high sucrose diet in mice. Taken together, these data show increased vascular mTORC1 signaling in obesity, but this vascular mTORC1 activation appears not to be required for the development of endothelial impairment in obesity.
    Keywords:  endothelial dysfunction; high fat diet; mTORC1; obesity
    DOI:  https://doi.org/10.1152/ajpregu.00113.2021
  4. Sci Adv. 2021 Jun;pii: eabf1068. [Epub ahead of print]7(27):
    Lacrimal gland budding requires PI3K-dependent suppression of EGF signaling.
    Qian Wang, Chenqi Tao, Abdul Hannan, Sungtae Yoon, Xuanyu Min, John Peregrin, Xiuxia Qu, Hongge Li, Honglian Yu, Jean Zhao, Xin Zhang.
      The patterning of epithelial buds is determined by the underlying signaling network. Here, we study the cross-talk between phosphoinositide 3-kinase (PI3K) and Ras signaling during lacrimal gland budding morphogenesis. Our results show that PI3K is activated by both the p85-mediated insulin-like growth factor (IGF) and Ras-mediated fibroblast growth factor (FGF) signaling. On the other hand, PI3K also promotes extracellular signal-regulated kinase (ERK) signaling via a direct interaction with Ras. Both PI3K and ERK are upstream regulators of mammalian target of rapamycin (mTOR), and, together, they prevent expansion of epidermal growth factor (EGF) receptor expression from the lacrimal gland stalk to the bud region. We further show that this suppression of EGF signaling is necessary for induction of lacrimal gland buds. These results reveal that the interplay between PI3K, mitogen-activated protein kinase, and mTOR mediates the cross-talk among FGF, IGF, and EGF signaling in support of lacrimal gland development.
    DOI:  https://doi.org/10.1126/sciadv.abf1068
  5. Hematol Oncol Clin North Am. 2021 Aug;pii: S0889-8588(21)00041-1. [Epub ahead of print]35(4): 807-826
    The Evolving Use of Phosphatidylinositol 3-Kinase Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.
    Benjamin L Lampson, Jennifer R Brown.
      B cells express 4 phosphatidylinositol 3-kinase (PI3K) isoforms and have a dependence on p110δ for survival. The design of isoform-selective inhibitors is possible, and pharmacologic inhibition of p110δ is toxic to neoplastic chronic lymphocytic leukemia (CLL) cells for both cell-intrinsic and cell-extrinsic reasons. Idelalisib is a first-in-class p110δ inhibitor that exhibits efficacy for the treatment of relapsed CLL irrespective of adverse prognostic features. Duvelisib is a p110γ/δ inhibitor with a similar efficacy and safety profile to idelalisib. Recent data indicate that umbralisib, a p110δ/CK-1ε dual inhibitor, is safe and effective when administered to patients with CLL.
    Keywords:  Chronic lymphocytic leukemia; Duvelisib; Idelalisib; PI3-kinase inhibitors; Parsaclisib; Umbralisib; Zandelisib
    DOI:  https://doi.org/10.1016/j.hoc.2021.03.009
  6. PLoS Comput Biol. 2021 Jun 30. 17(6): e1009125
    Inhibition of RPS6K reveals context-dependent Akt activity in luminal breast cancer cells.
    Cemal Erdem, Adrian V Lee, D Lansing Taylor, Timothy R Lezon.
      Aberrant signaling through insulin (Ins) and insulin-like growth factor I (IGF1) receptors contribute to the risk and advancement of many cancer types by activating cell survival cascades. Similarities between these pathways have thus far prevented the development of pharmacological interventions that specifically target either Ins or IGF1 signaling. To identify differences in early Ins and IGF1 signaling mechanisms, we developed a dual receptor (IGF1R & InsR) computational response model. The model suggested that ribosomal protein S6 kinase (RPS6K) plays a critical role in regulating MAPK and Akt activation levels in response to Ins and IGF1 stimulation. As predicted, perturbing RPS6K kinase activity led to an increased Akt activation with Ins stimulation compared to IGF1 stimulation. Being able to discern differential downstream signaling, we can explore improved anti-IGF1R cancer therapies by eliminating the emergence of compensation mechanisms without disrupting InsR signaling.
    DOI:  https://doi.org/10.1371/journal.pcbi.1009125
  7. Int J Mol Sci. 2021 Jun 28. pii: 6944. [Epub ahead of print]22(13):
    Feedback, Crosstalk and Competition: Ingredients for Emergent Non-Linear Behaviour in the PI3K/mTOR Signalling Network.
    Milad Ghomlaghi, Anthony Hart, Nhan Hoang, Sungyoung Shin, Lan K Nguyen.
      The PI3K/mTOR signalling pathway plays a central role in the governing of cell growth, survival and metabolism. As such, it must integrate and decode information from both external and internal sources to guide efficient decision-making by the cell. To facilitate this, the pathway has evolved an intricate web of complex regulatory mechanisms and elaborate crosstalk with neighbouring signalling pathways, making it a highly non-linear system. Here, we describe the mechanistic biological details that underpin these regulatory mechanisms, covering a multitude of negative and positive feedback loops, feed-forward loops, competing protein interactions, and crosstalk with major signalling pathways. Further, we highlight the non-linear and dynamic network behaviours that arise from these regulations, uncovered through computational and experimental studies. Given the pivotal role of the PI3K/mTOR network in cellular homeostasis and its frequent dysregulation in pathologies including cancer and diabetes, a coherent and systems-level understanding of the complex regulation and consequential dynamic signalling behaviours within this network is imperative for advancing biology and development of new therapeutic approaches.
    Keywords:  PI3K/mTOR signalling; cancer; crosstalk; feedback loop; nonlinear dynamics
    DOI:  https://doi.org/10.3390/ijms22136944
  8. Annu Rev Cell Dev Biol. 2021 Jul 01.
    Cell Biology of Canonical Wnt Signaling.
    Lauren V Albrecht, Nydia Tejeda-Muñoz, Edward M De Robertis.
      Wnt signaling has multiple functions beyond the transcriptional effects of β-catenin stabilization. We review recent investigations that uncover new cell physiological effects through the regulation of Wnt receptor endocytosis, Wnt-induced stabilization of proteins (Wnt-STOP), macropinocytosis, increase in lysosomal activity, and metabolic changes. Many of these growth-promoting effects of canonical Wnt occur within minutes and are independent of new protein synthesis. A key element is the sequestration of glycogen synthase kinase 3 (GSK3) inside multivesicular bodies and lysosomes. Twenty percent of human proteins contain consecutive GSK3 phosphorylation motifs, which in the absence of Wnt can form phosphodegrons for polyubiquitination and proteasomal degradation. Wnt signaling by either the pharmacological inhibition of GSK3 or the loss of tumor-suppressor proteins, such as adenomatous polyposis coli (APC) and Axin1, increases lysosomal acidification, anabolic metabolites, and macropinocytosis, which is normally repressed by the GSK3-Axin1-APC destruction complex. The combination of these cell physiological effects drives cell growth. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 37 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-cellbio-120319-023657
  9. Cancers (Basel). 2021 Jun 22. pii: 3120. [Epub ahead of print]13(13):
    PTEN Hamartoma Tumor Syndrome/Cowden Syndrome: Genomics, Oncogenesis, and Imaging Review for Associated Lesions and Malignancy.
    David D Dragoo, Ahmed Taher, Vincenzo K Wong, Ahmed Elsaiey, Nikita Consul, Hagar S Mahmoud, Bilal Mujtaba, Nir Stanietzky, Khaled M Elsayes.
      PTEN hamartoma tumor syndrome/Cowden syndrome (CS) is a rare autosomal dominant syndrome containing a germline PTEN mutation that leads to the development of multisystem hamartomas and oncogenesis. Benign tumors such as Lhermitte-Duclos disease and malignant tumors involving the breast, thyroid, kidneys, and uterus are seen in CS. Radiologists have an integral role in the comanagement of CS patients. We present the associated imaging findings and imaging screening recommendations. Knowledge of the types of cancers commonly seen in CS and their imaging findings can aid in early tumor recognition during cancer screening to help ensure near-normal life spans in CS patients.
    Keywords:  Cowden syndrome; PTEN; imaging review; multiple hamartoma syndrome
    DOI:  https://doi.org/10.3390/cancers13133120
  10. Science. 2021 07 02. 373(6550): 111-117
    Embryo-scale, single-cell spatial transcriptomics.
    Sanjay R Srivatsan, Mary C Regier, Eliza Barkan, Jennifer M Franks, Jonathan S Packer, Parker Grosjean, Madeleine Duran, Sarah Saxton, Jon J Ladd, Malte Spielmann, Carlos Lois, Paul D Lampe, Jay Shendure, Kelly R Stevens, Cole Trapnell.
      Spatial patterns of gene expression manifest at scales ranging from local (e.g., cell-cell interactions) to global (e.g., body axis patterning). However, current spatial transcriptomics methods either average local contexts or are restricted to limited fields of view. Here, we introduce sci-Space, which retains single-cell resolution while resolving spatial heterogeneity at larger scales. Applying sci-Space to developing mouse embryos, we captured approximate spatial coordinates and whole transcriptomes of about 120,000 nuclei. We identify thousands of genes exhibiting anatomically patterned expression, leverage spatial information to annotate cellular subtypes, show that cell types vary substantially in their extent of spatial patterning, and reveal correlations between pseudotime and the migratory patterns of differentiating neurons. Looking forward, we anticipate that sci-Space will facilitate the construction of spatially resolved single-cell atlases of mammalian development.
    DOI:  https://doi.org/10.1126/science.abb9536
  11. Sci Signal. 2021 Jan 19. pii: eaaz4382. [Epub ahead of print]14(666):
    NF-κB responds to absolute differences in cytokine concentrations.
    Minjun Son, Andrew G Wang, Hsiung-Lin Tu, Marie Oliver Metzig, Parthiv Patel, Kabir Husain, Jing Lin, Arvind Murugan, Alexander Hoffmann, Savaş Tay.
      Cells receive a wide range of dynamic signaling inputs during immune regulation, but how gene regulatory networks measure such dynamic inputs is not well understood. Here, we used microfluidic single-cell analysis and mathematical modeling to study how the NF-κB pathway responds to immune inputs that vary over time such as increasing, decreasing, or fluctuating cytokine signals. We found that NF-κB activity responded to the absolute difference in cytokine concentration and not to the concentration itself. Our analyses revealed that negative feedback by the regulatory proteins A20 and IκBα enabled differential responses to changes in cytokine dose by providing a short-term memory of previous cytokine concentrations and by continuously resetting kinase cycling and receptor abundance. Investigation of NF-κB target gene expression showed that cells exhibited distinct transcriptional responses under different dynamic cytokine profiles. Our results demonstrate how cells use simple network motifs and transcription factor dynamics to efficiently extract information from complex signaling environments.
  12. Cell Rep. 2021 Jun 29. pii: S2211-1247(21)00705-1. [Epub ahead of print]35(13): 109329
    p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino.
    Christina B Marney, Erik S Anderson, Mutayyaba Adnan, Kai-Lin Peng, Ya Hu, Nils Weinhold, Adam M Schmitt.
      Many long noncoding RNA (lncRNA) genes exist near cancer-associated loci, yet evidence connecting lncRNA functions to recurrent genetic alterations in cancer are lacking. Here, we report that DINO, the lncRNA transcribed from the cancer-associated DINO/CDKN1A locus, suppresses tumor formation independent of p21, the protein encoded at the locus. Loss of one or two alleles of Dino impairs p53 signaling and apoptosis, resulting in a haplo-insufficient tumor suppressor phenotype in genetically defined mouse models of tumorigenesis. A discrete region of the DINO/CDKN1A locus is recurrently hypermethylated in human cancers, silencing DINO but not CDKN1A, the gene encoding p21. Hypermethylation silences DINO, impairs p53 signaling pathway in trans, and is mutually exclusive with TP53 alterations, indicating that DINO and TP53 comprise a common tumor suppressor module. Therefore, DINO encodes a lncRNA essential for tumor suppression that is recurrently silenced in human cancers as a mechanism to escape p53-dependent tumor suppression.
    Keywords:  DINO; DNA methylation; cancer; long noncoding RNA; p53; tumor suppression
    DOI:  https://doi.org/10.1016/j.celrep.2021.109329
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