bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2025–01–05
thirteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. PTEN loss in glioma cell lines leads to increased extracellular vesicle biogenesis and PD-L1 cargo in a PI3K-dependent manner.
  2. Robust and inducible genome editing via an all-in-one prime editor in human pluripotent stem cells.
  3. Global organelle profiling reveals subcellular localization and remodeling at proteome scale.
  4. Lipidomic profiling of mouse brain and human neuron cultures reveals a role for Mboat7 in mTOR-dependent neuronal migration.
  5. High order expression dependencies finely resolve cryptic states and subtypes in single cell data.
  6. Dysregulation of mTOR signalling is a converging mechanism in lissencephaly.
  7. Degradation bottlenecks and resource competition in transiently and stably engineered mammalian cells.
  8. A Bayesian active learning platform for scalable combination drug screens.
  9. FAIR Data Cube, a FAIR data infrastructure for integrated multi-omics data analysis.
  10. FBP1 controls liver cancer evolution from senescent MASH hepatocytes.
  11. Paradoxical link between senescent cell state and liver cancer resolved.
  12. Hyperactive delta isoform of PI3Kinase enables long distance regeneration of adult rat corticospinal tract.
  13. Direct specification of lymphatic endothelium from mesenchymal progenitors.
  1. J Biol Chem. 2024 Dec 26. pii: S0021-9258(24)02645-0. [Epub ahead of print] 108143
    PTEN loss in glioma cell lines leads to increased extracellular vesicle biogenesis and PD-L1 cargo in a PI3K-dependent manner.
    Julio C Sanchez, Timothy M Pierpont, Dariana Argueta-Zamora, Kristin Wilson, Avery August, Richard A Cerione.
      Phosphatase and Tensin Homologue (PTEN) is one of the most frequently lost tumor suppressors in cancer and the predominant negative regulator of the PI3K/AKT signaling axis. A growing body of evidence has highlighted the loss of PTEN with immuno-modulatory functions including the upregulation of the programmed death ligand-1 (PD-L1), an altered tumor derived secretome that drives an immunosuppressive tumor immune microenvironment (TIME), and resistance to certain immunotherapies. Given their roles in immunosuppression and tumor growth, we examined whether the loss of PTEN would impact the biogenesis, cargo, and function of extracellular vesicles (EVs) in the context of the anti-tumor associated cytokine interferon-γ (IFN-γ). Through genetic and pharmacological approaches, we show that total cellular expression of PD-L1 is regulated by JAK/STAT signaling, not PI3K signaling. Instead, we observe that PTEN loss specifically upregulates cell surface levels of PD-L1 and enhances the biogenesis of EVs enriched with PD-L1 in a PI3K-dependent manner. We demonstrate that because of these changes, EVs derived from glioma cells lacking PTEN have a greater ability to suppress T cell receptor (TCR) signaling. Taken together, these findings provide important new insights into how the loss of PTEN can contribute to an immunosuppressive TIME, facilitate immune evasion, and highlight a novel role for PI3K signaling in the regulation of EV biogenesis and the cargo they contain.
    Keywords:  Glioblastoma; extracellular vesicles; immunosuppression; phosphatase and tensin homolog (PTEN); phosphatidylinositide 3‐kinase (PI 3‐kinase)
    DOI:  https://doi.org/10.1016/j.jbc.2024.108143
  2. Nat Commun. 2024 Dec 30. 15(1): 10824
    Robust and inducible genome editing via an all-in-one prime editor in human pluripotent stem cells.
    Youjun Wu, Aaron Zhong, Mega Sidharta, Tae Wan Kim, Bernny Ramirez, Benjamin Persily, Lorenz Studer, Ting Zhou.
      Prime editing (PE) allows for precise genome editing in human pluripotent stem cells (hPSCs), such as introducing single nucleotide modifications, small insertions or deletions at a specific genomic locus. Here, we systematically compare a panel of prime editing conditions in hPSCs and generate a potent prime editor, "PE-Plus", through co-inhibition of mismatch repair and p53-mediated cellular stress responses. We further establish an inducible prime editing platform in hPSCs by incorporating the PE-Plus into a safe-harbor locus and demonstrated temporal control of precise editing in both hPSCs and differentiated cells. By evaluating disease-associated mutations, we show that this platform allows efficient creation of both monoallelic and biallelic disease-relevant mutations in hPSCs. In addition, this platform enables the efficient introduction of single or multiple edits in one step, demonstrating potential for multiplex editing. Our method presents an efficient and controllable multiplex prime editing tool in hPSCs and their differentiated progeny.
    DOI:  https://doi.org/10.1038/s41467-024-55104-1
  3. Cell. 2024 Dec 26. pii: S0092-8674(24)01344-8. [Epub ahead of print]
    Global organelle profiling reveals subcellular localization and remodeling at proteome scale.
    Marco Y Hein, Duo Peng, Verina Todorova, Frank McCarthy, Kibeom Kim, Chad Liu, Laura Savy, Camille Januel, Rodrigo Baltazar-Nunez, Madhurya Sekhar, Shivanshi Vaid, Sophie Bax, Madhuri Vangipuram, James Burgess, Leila Njoya, Eileen Wang, Ivan E Ivanov, Janie R Byrum, Soorya Pradeep, Carlos G Gonzalez, Yttria Aniseia, Joseph S Creery, Aidan H McMorrow, Sara Sunshine, Serena Yeung-Levy, Brian C DeFelice, Shalin B Mehta, Daniel N Itzhak, Joshua E Elias, Manuel D Leonetti.
      Defining the subcellular distribution of all human proteins and their remodeling across cellular states remains a central goal in cell biology. Here, we present a high-resolution strategy to map subcellular organization using organelle immunocapture coupled to mass spectrometry. We apply this workflow to a cell-wide collection of membranous and membraneless compartments. A graph-based analysis assigns the subcellular localization of over 7,600 proteins, defines spatial networks, and uncovers interconnections between cellular compartments. Our approach can be deployed to comprehensively profile proteome remodeling during cellular perturbation. By characterizing the cellular landscape following HCoV-OC43 viral infection, we discover that many proteins are regulated by changes in their spatial distribution rather than by changes in abundance. Our results establish that proteome-wide analysis of subcellular remodeling provides key insights for elucidating cellular responses, uncovering an essential role for ferroptosis in OC43 infection. Our dataset can be explored at organelles.czbiohub.org.
    Keywords:  CRISPR; HCoV-OC43 coronavirus; cell biology; ferroptosis; k-NN graph; mass spectrometry; native organelle IP; protein localization; spatial proteomics; subcellular remodeling; viral infection
    DOI:  https://doi.org/10.1016/j.cell.2024.11.028
  4. Sci Transl Med. 2025 Jan;17(779): eadp5247
    Lipidomic profiling of mouse brain and human neuron cultures reveals a role for Mboat7 in mTOR-dependent neuronal migration.
    Isaac Tang, Ashna Nisal, Alex Reed, Timothy B Ware, Anide Johansen, Maha S Zaki, Benjamin F Cravatt, Joseph G Gleeson.
      Mutations in lipid regulator genes are a frequent cause of autism spectrum disorder, including those regulating phosphatidylinositol (PI) and phosphoinositide 3-kinase signaling. MBOAT7 encodes a key acyltransferase in PI synthesis and is mutated in an autism-related condition with neurodevelopmental delay and epilepsy. Using liquid chromatography-tandem mass spectrometry, we analyzed the PI-associated glycerolipidome in mice and humans during neurodevelopment and found dynamic regulation at times corresponding to neural apoptosis in the brains of Mboat7 knockout mice. Mboat7 function was necessary for polyunsaturated lipid synthesis and cortical neural migration, and loss resulted in massive accumulation of the precursor lysophosphatidylinositol and hyperactive mTOR signaling. Inhibiting mTOR signaling rescued migration defects. Our findings demonstrate roles for lipid remodeling during neurodevelopment and implicate lipid regulation in neuronal migration, revealing potential paths to treatment for MBOAT7 deficiency.
    DOI:  https://doi.org/10.1126/scitranslmed.adp5247
  5. Mol Syst Biol. 2025 Jan 02.
    High order expression dependencies finely resolve cryptic states and subtypes in single cell data.
    Abel Jansma, Yuelin Yao, Jareth Wolfe, Luigi Del Debbio, Sjoerd V Beentjes, Chris P Ponting, Ava Khamseh.
      Single cells are typically typed by clustering into discrete locations in reduced dimensional transcriptome space. Here we introduce Stator, a data-driven method that identifies cell (sub)types and states without relying on cells' local proximity in transcriptome space. Stator labels the same single cell multiply, not just by type and subtype, but also by state such as activation, maturity or cell cycle sub-phase, through deriving higher-order gene expression dependencies from a sparse gene-by-cell expression matrix. Stator's finer resolution is clear from analyses of mouse embryonic brain, and human healthy or diseased liver. Rather than only coarse-scale labels of cell type, Stator further resolves cell types into subtypes, and these subtypes into stages of maturity and/or cell cycle phases, and yet further into portions of these phases. Among cryptically homogeneous embryonic cells, for example, Stator finds 34 distinct radial glia states whose gene expression forecasts their future GABAergic or glutamatergic neuronal fate. Further, Stator's fine resolution of liver cancer states reveals expression programmes that predict patient survival. We provide Stator as a Nextflow pipeline and Shiny App.
    Keywords:  Cell Cycle Phases; Cell State; Higher-order Gene Expression Dependencies; Single-cell Transcriptomics; Structure Learning
    DOI:  https://doi.org/10.1038/s44320-024-00074-1
  6. Nature. 2025 Jan 01.
    Dysregulation of mTOR signalling is a converging mechanism in lissencephaly.
    Ce Zhang, Dan Liang, A Gulhan Ercan-Sencicek, Aybike S Bulut, Joelly Cortes, Iris Q Cheng, Octavian Henegariu, Sayoko Nishimura, Xinyuan Wang, A Buket Peksen, Yutaka Takeo, Caner Caglar, TuKiet T Lam, Merve Nur Koroglu, Anand Narayanan, Francesc Lopez-Giraldez, Danielle F Miyagishima, Ketu Mishra-Gorur, Tanyeri Barak, Katsuhito Yasuno, E Zeynep Erson-Omay, Cengiz Yalcinkaya, Guilin Wang, Shrikant Mane, Hande Kaymakcalan, Aslan Guzel, A Okay Caglayan, Beyhan Tuysuz, Nenad Sestan, Murat Gunel, Angeliki Louvi, Kaya Bilguvar.
      Cerebral cortex development in humans is a highly complex and orchestrated process that is under tight genetic regulation. Rare mutations that alter gene expression or function can disrupt the structure of the cerebral cortex, resulting in a range of neurological conditions1. Lissencephaly ('smooth brain') spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability2. However, the molecular mechanisms underlying disease pathogenesis remain unknown. Here we establish hypoactivity of the mTOR pathway as a clinically relevant molecular mechanism in lissencephaly spectrum disorders. We characterized two types of cerebral organoid derived from individuals with genetically distinct lissencephalies with a recessive mutation in p53-induced death domain protein 1 (PIDD1) or a heterozygous chromosome 17p13.3 microdeletion leading to Miller-Dieker lissencephaly syndrome (MDLS). PIDD1-mutant organoids and MDLS organoids recapitulated the thickened cortex typical of human lissencephaly and demonstrated dysregulation of protein translation, metabolism and the mTOR pathway. A brain-selective activator of mTOR complex 1 prevented and reversed cellular and molecular defects in the lissencephaly organoids. Our findings show that a converging molecular mechanism contributes to two genetically distinct lissencephaly spectrum disorders.
    DOI:  https://doi.org/10.1038/s41586-024-08341-9
  7. Nat Commun. 2025 Jan 02. 16(1): 328
    Degradation bottlenecks and resource competition in transiently and stably engineered mammalian cells.
    Jacopo Gabrielli, Roberto Di Blasi, Cleo Kontoravdi, Francesca Ceroni.
      Degradation tags, otherwise known as degrons, are portable sequences that can be used to alter protein stability. Here, we report that degron-tagged proteins compete for cellular degradation resources in engineered mammalian cells leading to coupling of the degradation rates of otherwise independently expressed proteins when constitutively targeted human degrons are adopted. We show the effect of this competition to be dependent on the context of the degrons. By considering different proteins, degron position and cellular hosts, we highlight how the impact of the degron on both degradation strength and resource coupling changes, with identification of orthogonal combinations. By adopting inducible bacterial and plant degrons we also highlight how controlled uncoupling of synthetic construct degradation from the native machinery can be achieved. We then build a genomically integrated capacity monitor tagged with different degrons and confirm resource competition between genomic and transiently expressed DNA constructs. This work expands the characterisation of resource competition in engineered mammalian cells to protein degradation also including integrated systems, providing a framework for the optimisation of heterologous expression systems to advance applications in fundamental and applied biological research.
    DOI:  https://doi.org/10.1038/s41467-024-55311-w
  8. Nat Commun. 2025 Jan 02. 16(1): 156
    A Bayesian active learning platform for scalable combination drug screens.
    Christopher Tosh, Mauricio Tec, Jessica B White, Jeffrey F Quinn, Glorymar Ibanez Sanchez, Paul Calder, Andrew L Kung, Filemon S Dela Cruz, Wesley Tansey.
      Large-scale combination drug screens are generally considered intractable due to the immense number of possible combinations. Existing approaches use ad hoc fixed experimental designs then train machine learning models to impute unobserved combinations. Here we propose BATCHIE, an orthogonal approach that conducts experiments dynamically in batches. BATCHIE uses information theory and probabilistic modeling to design each batch to be maximally informative based on the results of previous experiments. On retrospective experiments from previous large-scale screens, BATCHIE designs rapidly discover highly effective and synergistic combinations. In a prospective combination screen of a library of 206 drugs on a collection of pediatric cancer cell lines, the BATCHIE model accurately predicts unseen combinations and detects synergies after exploring only 4% of the 1.4M possible experiments. Further, the model identifies a panel of top combinations for Ewing sarcomas, which follow-up validation experiments confirm to be effective, including the rational and translatable top hit of PARP plus topoisomerase I inhibition. These results demonstrate that adaptive experiments can enable large-scale unbiased combination drug screens with a relatively small number of experiments. BATCHIE is open source and publicly available ( https://github.com/tansey-lab/batchie ).
    DOI:  https://doi.org/10.1038/s41467-024-55287-7
  9. J Biomed Semantics. 2024 Dec 28. 15(1): 20
    FAIR Data Cube, a FAIR data infrastructure for integrated multi-omics data analysis.
    Xiaofeng Liao, Thomas H A Ederveen, Anna Niehues, Casper de Visser, Junda Huang, Firdaws Badmus, Cenna Doornbos, Yuliia Orlova, Purva Kulkarni, K Joeri van der Velde, Morris A Swertz, Martin Brandt, Alain J van Gool, Peter A C 't Hoen.
       MOTIVATION: We are witnessing an enormous growth in the amount of molecular profiling (-omics) data. The integration of multi-omics data is challenging. Moreover, human multi-omics data may be privacy-sensitive and can be misused to de-anonymize and (re-)identify individuals. Hence, most biomedical data is kept in secure and protected silos. Therefore, it remains a challenge to re-use these data without infringing the privacy of the individuals from which the data were derived. Federated analysis of Findable, Accessible, Interoperable, and Reusable (FAIR) data is a privacy-preserving solution to make optimal use of these multi-omics data and transform them into actionable knowledge.
    RESULTS: The Netherlands X-omics Initiative is a National Roadmap Large-Scale Research Infrastructure aiming for efficient integration of data generated within X-omics and external datasets. To facilitate this, we developed the FAIR Data Cube (FDCube), which adopts and applies the FAIR principles and helps researchers to create FAIR data and metadata, to facilitate re-use of their data, and to make their data analysis workflows transparent, and in the meantime ensure data security and privacy.
    Keywords:  Data sovereignty; FAIR; FAIR Data Cube; Federated analysis; Metadata; Multi-omics
    DOI:  https://doi.org/10.1186/s13326-024-00321-2
  10. Nature. 2025 Jan 01.
    FBP1 controls liver cancer evolution from senescent MASH hepatocytes.
    Liver Cancer Collaborative
      Hepatocellular carcinoma (HCC) originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged by viruses or metabolic-dysfunction-associated steatohepatitis (MASH)1. While increasing HCC risk2, MASH triggers p53-dependent hepatocyte senescence3, which we found to parallel hypernutrition-induced DNA breaks. How this tumour-suppressive response is bypassed to license oncogenic mutagenesis and enable HCC evolution was previously unclear. Here we identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a p53 target that is elevated in senescent-like MASH hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human HCCs. FBP1 first declines in metabolically stressed premalignant disease-associated hepatocytes and HCC progenitor cells4,5, paralleling the protumorigenic activation of AKT and NRF2. By accelerating FBP1 and p53 degradation, AKT and NRF2 enhance the proliferation and metabolic activity of previously senescent HCC progenitors. The senescence-reversing and proliferation-supportive NRF2-FBP1-AKT-p53 metabolic switch, operative in mice and humans, also enhances the accumulation of DNA-damage-induced somatic mutations needed for MASH-to-HCC progression.
    DOI:  https://doi.org/10.1038/s41586-024-08317-9
  11. Nature. 2025 Jan 01.
    Paradoxical link between senescent cell state and liver cancer resolved.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-04137-z
  12. Mol Ther. 2025 Jan 01. pii: S1525-0016(24)00838-4. [Epub ahead of print]
    Hyperactive delta isoform of PI3Kinase enables long distance regeneration of adult rat corticospinal tract.
    Karova Kristyna, Polcanova Zuzana, Knight Lydia, Suchankova Stepanka, Nieuwenhuis Bart, Holota Radovan, Herynek Vit, Machova Urdzikova Lucia, Turecek Rostislav, Kwok C Jessica, Joelle van den Herik, Verhaagen Joost, Eva Richard, Fawcett W James, Jendelova Pavla.
      Neurons in the central nervous system (CNS) lose regenerative potential with maturity, leading to minimal corticospinal tract (CST) axon regrowth after spinal cord injury (SCI). In young rodents, knockdown of PTEN, which antagonises PI3K signalling by hydrolysing PIP3, promotes axon regeneration following SCI. However, this effect diminishes in adults, potentially due to lower PI3K activation leading to reduced PIP3. This study explores if increased PIP3 generation can promote long-distance regeneration in adults. We used a hyperactive PI3K, PI3Kδ (PIK3CD), to boost PIP3 levels in mature cortical neurons and assessed CST regeneration after SCI. Adult rats received AAV1-PIK3CD and AAV1-eGFP, or AAV1-eGFP alone, in the sensorimotor cortex concurrent with a C4 dorsal SCI. Transduced neurons showed increased pS6 levels, indicating elevated PI3K/Akt/mTOR signalling. CST regeneration, confirmed with retrograde tracing, was evaluated up to 16 weeks post-injury. At 12 weeks, ∼100 axons were present at lesion sites, doubling to 200 by 16 weeks, with regeneration indices of 0.1 and 0.2, respectively. Behavioural tests showed significant improvements in paw reaching, grip strength, and ladder rung walking in PIK3CD-treated rats, corroborated by electrophysiological recordings of cord dorsum potentials and distal flexor muscles EMG. Thus, PI3Kδ upregulation in adult cortical neurons enhances axonal regeneration and functional recovery post-SCI.
    DOI:  https://doi.org/10.1016/j.ymthe.2024.12.040
  13. Nat Cardiovasc Res. 2025 Jan 02.
    Direct specification of lymphatic endothelium from mesenchymal progenitors.
    Irina-Elena Lupu, David E Grainger, Nils Kirschnick, Sarah Weischer, Erica Zhao, Ines Martinez-Corral, Hans Schoofs, Marie Vanhollebeke, Grace Jones, Jonathan Godwin, Aden Forrow, Ines Lahmann, Paul R Riley, Thomas Zobel, Kari Alitalo, Taija Mäkinen, Friedemann Kiefer, Oliver A Stone.
      During embryogenesis, endothelial cells (ECs) are generally described to arise from a common pool of progenitors termed angioblasts, which diversify through iterative steps of differentiation to form functionally distinct subtypes of ECs. A key example is the formation of lymphatic ECs (LECs), which are thought to arise largely through transdifferentiation from venous endothelium. Opposing this model, here we show that the initial expansion of mammalian LECs is primarily driven by the in situ differentiation of mesenchymal progenitors and does not require transition through an intermediate venous state. Single-cell genomics and lineage-tracing experiments revealed a population of paraxial mesoderm-derived Etv2+Prox1+ progenitors that directly give rise to LECs. Morphometric analyses of early LEC proliferation and migration, and mutants that disrupt lymphatic development supported these findings. Collectively, this work establishes a cellular blueprint for LEC specification and indicates that discrete pools of mesenchymal progenitors can give rise to specialized subtypes of ECs.
    DOI:  https://doi.org/10.1038/s44161-024-00570-5
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