bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2025–06–15
fourteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
  2. MatriCom: a scRNA-Seq data mining tool to infer ECM-ECM and cell-ECM communication systems.
  3. Brieflow: An Integrated Computational Pipeline for High-Throughput Analysis of Optical Pooled Screening Data.
  4. Diet-induced obesity promotes endothelial cell desensitization to VEGF-A and permanent islet vessel dysfunction in mice.
  5. BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction.
  6. Signalomics for molecular tumor boards and precision oncology of breast and gynecological cancers.
  7. Biosensor for monitoring PTEN activity in biological systems.
  8. First report of successful pregnancies after treatment with alpelisib for PIK3CA-related overgrowth spectrum.
  9. Stem cell fate decisions: Substates and attractors.
  10. Promoting vascular stability through Src inhibition and Tie2 activation: A model-based analysis.
  11. Reversal of cerebrovascular anomalies in a zebrafish model of vein of Galen aneurysm.
  12. Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis.
  13. Increasing mass spectrometry throughput using time-encoded sample multiplexing.
  14. The fifth era of science: Artificial scientific intelligence.
  1. Dev Cell. 2025 May 30. pii: S1534-5807(25)00319-3. [Epub ahead of print]
    AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
    Yann Cormerais, Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Jong Shin, Benjamin Stefadu, Jean Personnaz, Sandra Schrötter, Jessica Freed, Angelica D'Amore, Emma R Martin, Catherine L Salussolia, Mustafa Sahin, Suchithra Menon, Vanessa Byles, Brendan D Manning.
      Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates diverse growth signals to regulate cell and tissue growth. How the molecular mechanisms regulating mTORC1 signaling-established through biochemical and cell biological studies-function under physiological states in specific mammalian tissues is undefined. Here, we characterize a genetic mouse model lacking the five phosphorylation sites on the tuberous sclerosis complex 2 (TSC2) protein through which the growth factor-stimulated protein kinase AKT can activate mTORC1 signaling in cell culture models. These phospho-mutant mice (TSC2-5A) are developmentally normal but exhibit reduced body weight and the weight of specific organs, such as the brain and skeletal muscle, associated with cell-intrinsic decreases in growth factor-stimulated mTORC1 signaling. The TSC2-5A mice demonstrate that TSC2 phosphorylation is a primary mechanism of mTORC1 regulation in response to exogenous signals in some, but not all, tissues and provide a genetic tool to study the physiological regulation of mTORC1.
    Keywords:  PI3K; RHEB; feeding; insulin; lean mass; lysosome; microcephaly; myotubes; neurons; phosphoinositide 3-kinase
    DOI:  https://doi.org/10.1016/j.devcel.2025.05.008
  2. J Cell Sci. 2025 Jun 12. pii: jcs.263927. [Epub ahead of print]
    MatriCom: a scRNA-Seq data mining tool to infer ECM-ECM and cell-ECM communication systems.
    Rijuta Lamba, Asia M Paguntalan, Petar B Petrov, Alexandra Naba, Valerio Izzi.
      The ECM is a complex meshwork of proteins forming the framework of all multicellular organisms. Protein interactions are critical to building and remodeling the ECM meshwork, while interactions between ECM proteins and receptors are essential to initiate signal transduction. Here, we present MatriCom, a web application (https://matrinet.shinyapps.io/matricom) and a companion R package, devised to infer communications between ECM components and between different cell populations and the ECM from scRNA-Seq datasets. MatriCom relies on a unique database, MatriComDB, of over 25,000 curated interactions involving matrisome components to impute interactions from expression data. MatriCom offers the option to query user-generated or open-access datasets sourced from large sequencing efforts. MatriCom also accounts for specific rules governing ECM protein interactions. We illustrate how MatriCom can generate novel biological insights by building the first human kidney matrisome communication network. Last, applied to a panel of 46 scRNA-Seq datasets of healthy adult tissues, we demonstrate how MatriCom can shed light on the mechanisms of conservation and diversification of ECM assemblies and cell/ECM interactions.
    Keywords:  Co-expression; Extracellular Matrix; Matrisome; Network analysis; Protein-protein interactions
    DOI:  https://doi.org/10.1242/jcs.263927
  3. bioRxiv. 2025 May 27. pii: 2025.05.26.656231. [Epub ahead of print]
    Brieflow: An Integrated Computational Pipeline for High-Throughput Analysis of Optical Pooled Screening Data.
    Matteo Di Iernardo, Roshan S Kern, Alexa Mallar, Andrew Nutter-Upham, Paul C Blainey, Iain Cheeseman.
      Optical pooled screening (OPS) has emerged as a powerful technique for functional genomics, enabling researchers to link genetic perturbations with complex cellular morphological phenotypes at unprecedented scale. However, OPS data analysis presents challenges due to massive datasets, complex multi-modal integration requirements, and the absence of standardized frameworks. Here, we present Brieflow, a computational pipeline for end-to-end analysis of fixed-cell optical pooled screening data. We demonstrate Brieflow's capabilities through reanalysis of a CRISPR-Cas9 screen encompassing 5,072 fitness-conferring genes, processing more than 70 million cells with multiple phenotypic markers. Our analysis reveals functional gene relationships that were missed in the original study, uncovering coherent biological insights related to mitochondrial function, mRNA processing, vesicular trafficking, and MYC transcriptional control, amongst others. The modular design and open-source implementation of Brieflow facilitates the integration of novel analytical components while ensuring computational reproducibility and improved performance for the use of high-content phenotypic screening in biological discovery.
    DOI:  https://doi.org/10.1101/2025.05.26.656231
  4. J Clin Invest. 2025 Jun 05. pii: e177601. [Epub ahead of print]
    Diet-induced obesity promotes endothelial cell desensitization to VEGF-A and permanent islet vessel dysfunction in mice.
    Yan Xiong, Andrea Dicker, Montse Visa, Erwin Ilegems, Per-Olof Berggren.
      Pancreatic islet microvasculature is essential for optimal islet function and glucose homeostasis. However, islet vessel pathogenesis in obesity and its role in the manifestation of metabolic disorders remain understudied. Here, we depict the time-resolved decline of intra-islet endothelial cell responsiveness to vascular endothelial cell growth factor A (VEGF-A) and islet vessel function in a mouse model of diet-induced obesity. Longitudinal imaging of sentinel islets transplanted into mouse eyes revealed substantial vascular remodeling and diminished VEGF-A response in islet endothelial cells after 12 weeks of western diet (WD) feeding. This led to islet vessel barrier dysfunction and hemodynamic dysregulation, delaying transportation of secreted insulin into the blood. Notably, islet vessels exhibited a metabolic memory of previous WD feeding. Neither VEGF-A sensitivity nor the other vascular alterations was fully restored by control diet (CD) refeeding, resulting in modest yet significant impairment in glucose clearance despite normalized insulin sensitivity. Mechanistic analysis implicated hyperactivation of atypical protein kinase C (aPKC) under both WD and recovery conditions, which inhibited VEGF receptor 2 (VEGFR2) internalization and blunted VEGF-A triggered signal transduction in endothelial cells. In summary, prolonged WD feeding causes irreversible islet endothelial cell desensitization to VEGF-A and islet vessel dysfunction, directly undermining glucose homeostasis.
    Keywords:  Diabetes; Endocrinology; Endothelial cells; Metabolism; Molecular pathology; Vascular biology
    DOI:  https://doi.org/10.1172/JCI177601
  5. Science. 2025 Jun 12. eadq2004
    BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction.
    Dhirendra K Simanshu, Rui Xu, James P Stice, Daniel J Czyzyk, Siyu Feng, John-Paul Denson, Erin Riegler, Yue Yang, Cathy Zhang, Sofia Donovan, Brian P Smith, Maria Abreu-Blanco, Ming Chen, Cindy Feng, Lijuan Fu, Dana Rabara, Lucy C Young, Marcin Dyba, Wupeng Yan, Ken Lin, Samar Ghorbanpoorvalukolaie, Erik K Larsen, Wafa Malik, Allison Champagne, Katie Parker, Jin Hyun Ju, Stevan Jeknic, Dominic Esposito, David M Turner, Felice C Lightstone, Bin Wang, Paul M Wehn, Keshi Wang, Andrew G Stephen, Anna E Maciag, Aaron N Hata, Kerstin W Sinkevicius, Dwight V Nissley, Eli M Wallace, Frank McCormick, Pedro J Beltran.
      BBO-10203 is an orally available drug that covalently and specifically binds to the RAS-binding domain of phosphoinositide 3-kinase α (PI3Kα), preventing its activation by HRAS, NRAS, and KRAS. It inhibited PI3Kα activation in tumors with oncogenic mutations in KRAS or PIK3CA, and in tumors with human epidermal growth factor receptor 2 (HER2) amplification or overexpression. In preclinical models, BBO-10203 caused significant tumor growth inhibition across multiple tumor types and showed enhanced efficacy in combination with inhibitors of cyclin-dependent kinase 4/6 (CDK4/6), estrogen receptor (ER), HER2 and KRAS-G12C mutant, including in tumors harboring mutations in Kelch-like ECH-associated protein 1 (KEAP1) and Serine/Threonine Kinase 11 (STK11). Notably, these antitumor effects occurred without inducing hyperglycemia, as insulin signaling does not depend on RAS-mediated PI3Kα activation to promote glucose uptake.
    DOI:  https://doi.org/10.1126/science.adq2004
  6. Mol Syst Biol. 2025 Jun 09.
    Signalomics for molecular tumor boards and precision oncology of breast and gynecological cancers.
    Tatiana V Denisenko, Anna E Ivanova, Alexey Koval, Denis N Silachev, Lee Jia, Gennadiy T Sukhikh, Vladimir L Katanaev.
      Precision oncology led to the establishment and widespread application of molecular tumor boards (MTBs)-multidisciplinary units combining molecular and clinical assessment of individual cancer cases for swift selection of personalized treatments. Whole-exome or gene panel sequencing, combined with transcriptomic, immunohistochemical, and other molecular analyses, often permits dissection of molecular drivers of a tumor and identification of its potential targetable vulnerabilities, instructing clinical oncologists on sometimes unconventional treatment options. However, cancer drivers are often unleashed mutation-independently, especially in breast and gynecological cancers, and deleterious mutations are not always pathogenic. To complement the MTB arsenal, we chart here the molecular toolset we call Signalomics that permits fast and robust assessment of a panel of oncogenic signaling pathways in fresh tumor samples. Using transcriptional reporters introduced in primary tumor cells, this approach identifies the pathways overactivated in a given tumor and validates their sensitivity to targeted therapies, providing actionable insights for personalized treatment strategies. Integration of Signalomics into MTB workflows bridges the gap between molecular profiling and functional pathway analysis, refining clinical treatment decisions and advancing precision oncology.
    Keywords:  Breast and Gynecological Cancers; Molecular Tumor Board; Oncogenic Signaling Pathways; Precision Oncology; Signalomics
    DOI:  https://doi.org/10.1038/s44320-025-00125-1
  7. Trends Biochem Sci. 2025 Jun 11. pii: S0968-0004(25)00110-0. [Epub ahead of print]
    Biosensor for monitoring PTEN activity in biological systems.
    Tomer Kagan, Tal Laviv.
      
    DOI:  https://doi.org/10.1016/j.tibs.2025.05.006
  8. Eur J Hum Genet. 2025 Jun 06.
    First report of successful pregnancies after treatment with alpelisib for PIK3CA-related overgrowth spectrum.
    Gabriel Morin, Antoine Fraissenon, Caroline Chopinet, Estelle Balducci, Sophie Kaltenbach, Patrick Villarese, Vahid Asnafi, Laurent Guibaud, Guillaume Canaud.
      Alpelisib is a selective PI3Kα inhibitor approved for treating PIK3CA-related overgrowth spectrum (PROS), a group of rare malformation disorders. Given that PI3Kα is a ubiquitous protein involved in cell proliferation, understanding the long-term impact of alpelisib on fertility is of critical importance. Here, we report the favorable outcomes of three pregnancies in PROS patients after prolonged treatment with alpelisib. Although disease progression was observed in all three patients during pregnancy, vascular malformations remained sensitive to alpelisib without evidence of secondary resistance upon resuming treatment. In conclusion, we provide the first evidence that alpelisib does not appear to affect fertility in female patients with PROS.
    DOI:  https://doi.org/10.1038/s41431-025-01885-y
  9. Stem Cell Reports. 2025 Jun 10. pii: S2213-6711(25)00136-5. [Epub ahead of print]20(6): 102532
    Stem cell fate decisions: Substates and attractors.
    James E Mason, Xiaokai Nie, Daniel Coca, Peter W Andrews.
      Heterogeneity of gene expression is a characteristic of stem cell populations. Here, we review our own findings with human pluripotent stem cells, emphasizing their capacity to occupy distinct metastable substates that influence their differentiation outcomes. Experimental studies, such as single-cell transcriptomics and analyses of marker dynamics, demonstrate the transient and dynamic nature of these substates. Based on a novel approach to model sequences of fluorescent marker distributions over time, we suggest that transitions between these substates may be governed by deterministic chaos in addition to stochastic fluctuations of gene expression, both of which likely contribute to the observed dynamic behavior.
    Keywords:  deterministic chaos; differentiation; human; pluripotent stem cells; substates
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102532
  10. iScience. 2025 Jun 20. 28(6): 112625
    Promoting vascular stability through Src inhibition and Tie2 activation: A model-based analysis.
    Yu Zhang, Christopher D Kontos, Brian H Annex, Aleksander S Popel.
      Dysregulated angiogenesis signaling leads to pathological vascular growth and leakage, and is a hallmark of many diseases including cancer and ocular diseases. In peripheral arterial disease, the concomitant increase in vascular permeability presents significant challenges in therapeutic efforts to improve perfusion by stimulating vascular growth. Building a mechanistic understanding of the endothelial control of vascular growth and permeability signaling is crucial to guide our efforts to identify therapeutic strategies that permit blood vessel growth while maintaining vascular stability. We develop a mechanistic systems biology model of the endothelial signaling network formed by the vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-Tie pathways, two major signaling pathways regulating vascular growth and stability. Our model, calibrated and validated against experimental data, reveals the mechanisms through which chronic Ang1 stimulation protects endothelial cells from VEGF-induced hyperpermeability, and predicts that combining Src inhibition with Tie2 activation can inhibit vascular leakage without disturbing angiogenesis signaling.
    Keywords:  Bioinformatics; Biological sciences; Natural sciences; Pharmacoinformatics
    DOI:  https://doi.org/10.1016/j.isci.2025.112625
  11. Nat Cardiovasc Res. 2025 Jun 12.
    Reversal of cerebrovascular anomalies in a zebrafish model of vein of Galen aneurysm.
    Edwige Martin-Valiente, Yao Du, Chloé Goemans, Michelle America, Egor Zindy, Myckel Adam, Benoit Scheid, Miikka Vikkula, Boris Lubicz, Benoit Vanhollebeke, Nicolas Baeyens.
      Congenital vascular malformations result from abnormal development of the vascular tree, with the aneurysmal malformation of the vein of Galen (VGAM) being the most prevalent neurovascular malformation in neonates, associated with poor outcomes. This condition is linked to germline mutations in the RASA1 and EPHB4 genes, although the underlying developmental mechanisms remain unclear. Here we generate zebrafish models lacking rasa1a and ephb4a that replicate the genetic and structural features of VGAMs. Our findings connect the development of malformations to insufficient fusion of precursor blood vessels, a process regulated by blood flow and the responses of endothelial cells. RASA1 deficiency destabilizes the homeostatic response to blood flow and contributes to impaired flow-mediated activation of MAPK and phosphatidylinositol-3-kinase signaling. By pharmacologically targeting these signaling pathways in mutant models, we restore normal fusion in existing malformations, offering potential new strategies for treating VGAMs and similar vascular remodeling disorders.
    DOI:  https://doi.org/10.1038/s44161-025-00659-5
  12. bioRxiv. 2025 Jun 01. pii: 2025.05.28.656689. [Epub ahead of print]
    Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis.
    Adrien Grimont, David J Falvo, Whitney J Sisso, Paul Zumbo, Christopher W Chan, Francisco Santos, Grace Pan, Megan Cleveland, Tomer M Yaron, Alexa Osterhoudt, Yinuo Meng, Maria Paz Zafra, William B Fall, Andre F Rendeiro, Erika Hissong, Rhonda K Yantiss, Doron Betel, Mark A Magnuson, Steven D Leach, Anil K Rustgi, Lukas E Dow, Rohit Chandwani.
      Inflammation in the pancreas drives acinar-to-ductal metaplasia (ADM), a progenitor-like state that can be hijacked by mutant Kras in the formation of pancreatic cancer (PDAC). How these cell fate decisions vary according to KRAS mutation remains poorly understood. To define mutation-specific lineage reversion and tumor initiation, we implement novel Ptf1a-TdTomato mice and multiple KRAS mutants across an array of genetic, pharmacologic, and inflammatory perturbations in vivo . Whereas KRAS G12D co-opts injury to enable lineage reversion, enhancer reprogramming, and tumor initiation, KRAS G12R/V can initiate but not sustain dedifferentiated and neoplastic transcriptional and epigenetic programs. We find the KRAS G12R/V defects consist of a failure to invoke robust EGFR signaling and activate Rac1/Vav1, with constitutive Akt activation in vivo sufficient to rescue the tumorigenic potential of KRAS G12R . As the marked heterogeneity among KRAS variants begins early in tumorigenesis, these data are crucial to understanding mutation-specific oncogenic trajectories and directing the implementation of KRAS -directed therapeutics.
    SIGNIFICANCE: Defining how KRAS mutants drive distinct outcomes in human pancreatic cancer is critical for developing allele-specific therapeutic approaches. This study unveils a hierarchy among KRAS G12D , KRAS G12V , and KRAS G12R to drive tumor initiation, owing to heterogeneous activation of EGFR, PI3K/AKT, and RAC1 signaling, thus revealing mutation-specific evolutionary paths in pancreatic tumorigenesis.
    DOI:  https://doi.org/10.1101/2025.05.28.656689
  13. bioRxiv. 2025 May 27. pii: 2025.05.22.655515. [Epub ahead of print]
    Increasing mass spectrometry throughput using time-encoded sample multiplexing.
    Jason Derks, Kevin McDonnell, Nathan Wamsley, Peyton Stewart, Maddy Yeh, Harrison Specht, Nikolai Slavov.
      Liquid chromatography-mass spectrometry (LC-MS) can enable precise and accurate quantification of analytes at high-sensitivity, but the rate at which samples can be analyzed remains limiting. Throughput can be increased by multiplexing samples in the mass domain with plexDIA, yet multiplexing along one dimension will only linearly scale throughput with plex. To enable combinatorial-scaling of proteomics throughput we developed a complementary multiplexing strategy in the time domain, termed `timePlex'. timePlex staggers and overlaps the separation periods of individual samples. This strategy is orthogonal to isotopic multiplexing, which enables combinatorial multiplexing in mass and time domains when paired together and thus multiplicatively increased throughput. We demonstrate this with 3-timePlex and 3-plexDIA, enabling the multiplexing of 9 samples per LC-MS run, and 3-timePlex and 9-plexDIA exceeding 500 samples / day with a combinatorial 27-plex. Crucially, timePlex supports sensitive analyses, including of single cells. These results establish timePlex as a methodology for label-free multiplexing and for combinatorially scaling the throughput of LC-MS proteomics. We project this combined approach will eventually enable an increase in throughput exceeding 1,000 samples / day.
    DOI:  https://doi.org/10.1101/2025.05.22.655515
  14. PLoS Biol. 2025 Jun 10. 23(6): e3003230
    The fifth era of science: Artificial scientific intelligence.
    Nina Miolane.
      The era of artificial scientific intelligence is here. As algorithms generate discoveries at scale, what role remains for human scientists?
    DOI:  https://doi.org/10.1371/journal.pbio.3003230
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