bims-pideca 2026-03-15 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2026–03–15
fourteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU

Current and emerging pharmacotherapies for treating vascular malformations.
Genetic recording and in situ readout of single-cell signaling memory.
Transcriptional control of PPP2CB by YAP1 and TEAD1 mediates AMPK inhibition and mTORC1 activation in vascular smooth muscle cells.
A tandem recruitment site in the pseudokinase scaffold PEAK3 is subject to phosphorylation-dependent regulation and cancer-associated mutations.
AKT is necessary for neuronal hypertrophy and epilepsy caused by Pten knockout.
Gene regulatory networks: from correlative models to causal explanations.
Tuberous sclerosis complex.
Flow-induced Klf4-Akt signaling links EC cycling to mural cell defects in arterial-venous malformations.
Tuberous sclerosis complex.
Pareto optimality reveals an atlas of cellular archetypes.
Plakoglobin transmits tension across VE-cadherin for vascular leak formation and leukocyte diapedesis.
Scalable nonparametric clustering with unified marker gene selection for single-cell RNA-seq data.
Epilepsy in pediatric patients with PTEN hamartoma tumor syndrome: First step in recommendations for clinical management.
Guidelines for Evaluating Endothelial Function in Vascular Tissue.

Expert Rev Clin Pharmacol. 2026 Mar 08.

Current and emerging pharmacotherapies for treating vascular malformations.

Emmanuel Seront, An Van Damme, Julien Coulie, Laurence M Boon, Miikka Vikkula.

   INTRODUCTION: Vascular malformations are chronic, often progressive disorders for which conventional procedures frequently provide incomplete control. Advances in molecular genetics have revealed recurrent pathway alterations that now enable mechanism-based pharmacologic treatment.
AREAS COVERED: This narrative review summarizes current and emerging targeted therapies for vascular malformations, including mTOR, PI3K, MEK, anti-angiogenic, and genotype-specific inhibitors. Vascular malformations - capillary, lymphatic, venous, and arteriovenous - are increasingly recognized as disorders driven by dysregulation of the PI3K - AKT - mTOR and RAS - MAPK - ERK pathways, supporting rational repurposing of targeted anticancer drugs. We discuss clinical evidence, limitations, and practical considerations for sirolimus, PI3K inhibitors, thalidomide, MEK inhibitors, and KRAS-directed agents, as well as emerging combination and intermittent strategies to balance efficacy and toxicity. The review is based on a structured PubMed/MEDLINE search up to December 2025, prioritizing original translational studies, prospective trials, and large clinical series.
EXPERT OPINION: Targeted therapies are shifting management from procedure-centered to biology-guided care. Future progress depends on standardized molecular testing, patient-centered outcomes, and optimized treatment duration to achieve durable disease control with acceptable long-term toxicity.

Keywords:  TRAMAV; Targeted therapies; VASE; sirolimus; thalidomide; trametinib

DOI:  https://doi.org/10.1080/17512433.2026.2641807
Nat Chem Biol. 2026 Mar 11.

Genetic recording and in situ readout of single-cell signaling memory.

Kai Hao, Yunzheng Liu, Mykel Barrett, Zainalabedin Samadi, Amirhossein Zarezadeh, Yuka McGrath, Magdalena Zernicka-Goetz, Amjad Askary.

Intensity and duration of biological signals encode a few pathways to direct diverse cellular behaviors, yet quantifying these features in single cells remains difficult. To address this challenge, we developed INSCRIBE, which uses a CRISPR base editor to mutate genomic targets at rates proportional to signaling activity. Edits are recovered at the endpoint through a new ratiometric readout strategy from images of two fluorescence channels. We engineered human cells to record WNT and BMP activity. Following defined exogenous stimulations, INSCRIBE accurately recovered signal intensity in dose-response experiments and exposure duration in time-course experiments. Applying INSCRIBE revealed a persistent memory in the BMP pathway, where progeny of high-responding cells remained more sensitive to subsequent BMP stimulation for up to 3 weeks. Together, our results establish a scalable platform for genetic recording and in situ readout of signaling activity in single cells, advancing quantitative analysis of cell-cell communication during development and disease.

DOI: https://doi.org/10.1038/s41589-026-02168-3
iScience. 2026 Mar 20. 29(3): 114996

Transcriptional control of PPP2CB by YAP1 and TEAD1 mediates AMPK inhibition and mTORC1 activation in vascular smooth muscle cells.

Sanjana Kumariya, Joanna Stuck, Arturo Grano de Oro, Islam Osman.

  We previously demonstrated that the transcriptional co-factor Yes-associated protein 1 (YAP1) promotes vascular smooth muscle cell (VSMC) phenotypic switching and neointima formation. However, the underlying mechanisms remain unclear. Here, using YAP1 silencing and overexpression assays in human VSMCs, we demonstrate that YAP1 is necessary and sufficient to activate mammalian target of rapamycin complex 1 (mTORC1) and that mTORC1 activity is required for YAP1-induced VSMC proliferation. Mechanistically, we report that YAP1 inhibits AMP-activated protein kinase (AMPK), a negative regulator of mTORC1, thereby relieving AMPK-mediated suppression of mTORC1. We identify the protein phosphatase 2A catalytic subunit PPP2CB as a YAP1-regulated transcriptional target that contributes to AMPK inhibition and mTORC1 activation. We further show that a transcription factor, transcriptional enhancer activator domain 1 (TEAD1), mediates YAP1-dependent PPP2CB expression and that the upstream AMPK kinase CAMKK2 is required for YAP1-dependent modulation of AMPK/mTORC1 signaling. Together, these results define a YAP1/AMPK/mTORC1 signaling axis that drives VSMC proliferation, with potential broader relevance given the ubiquitous expression of these signaling molecules.

Keywords:  classification description; molecular mechanism of gene regulation; vascular remodeling

DOI:  https://doi.org/10.1016/j.isci.2026.114996
J Biol Chem. 2026 Mar 10. pii: S0021-9258(26)00235-8. [Epub ahead of print] 111365

A tandem recruitment site in the pseudokinase scaffold PEAK3 is subject to phosphorylation-dependent regulation and cancer-associated mutations.

Tianyue Zhao, Jianmei Hou, Changyuan Hu, Thomas R Cotton, Roger J Daly.

  The PEAK protein family, comprising PEAK1-3, are pseudokinase scaffolds that regulate cell proliferation and motility via recruitment of specific effectors. For PEAK3, the latter include the adaptor proteins Grb2 and CrkII and the Arf GTPase-activating protein (ArfGAP) ASAP1. PEAK3 exhibits a tandem site spanning a CrkII SH3 domain binding sequence and phosphorylation-dependent 14-3-3 recruitment motif at serine 69 (S69), with 14-3-3 binding mediating a negative control 'switch' on PEAK3 signalling. However, whether this control switch is subject to (patho)physiological regulation has remained unclear. Here, using MCF-10A breast epithelial cells as a model system, we demonstrate that S69 phosphorylation occurs predominantly in the cytoplasm and is subject to growth factor regulation, being enhanced by both EGF and insulin stimulation but with distinct temporal dynamics. We identify Ca2+/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) as key mediators of this phosphorylation event. Disruption of the pS69/14-3-3 interaction in the PEAK3 S69A mutant leads to elevated basal Erk phosphorylation, altered EGF-induced Erk and Akt activation kinetics, partial epithelial-to-mesenchymal transition, and increased Arf1 activation. Interrogation of the COSMIC database identified cancer-associated mutations in the tandem recruitment site, and their functional characterization revealed a subset that confer enhanced Grb2/ASAP1 binding and migration potential compared to wildtype PEAK3. Interestingly, amongst the cancer mutations, PEAK3 R66P and R66Q lost 14-3-3 binding in vivo, but L55P retained it. Together, our study reveals that the tandem PEAK3 regulatory site is subject to physiological control and is also mutated in cancer.

Keywords:  cell signaling; protein-protein interaction; serine/threonine phosphorylation; signal transduction

DOI:  https://doi.org/10.1016/j.jbc.2026.111365
Brain. 2026 Mar 09. pii: awag098. [Epub ahead of print]

AKT is necessary for neuronal hypertrophy and epilepsy caused by Pten knockout.

Mackenzi L Prina, Andrew R Goyette, Asan F Abdulkareem, Kamran Tariq, Nathan Burgess, Jianmin Su, Wei Wang, Meijie Li, Lucky L Drucker, Helena H Seo, Nicole M Desmet, Linda Overstreet-Wadiche, Bridget Shafit-Zagardo, Matthew C Weston, Bryan W Luikart.

  Phosphatase and tensin homolog on chromosome 10 (PTEN) is a key negative regulator of the AKT/mTOR signaling pathway. Mutations in PTEN are highly implicated in Autism Spectrum Disorder (ASD), epilepsy, congenital hydrocephaly, and macrocephaly. While the conditional genetic knockout of Pten in murine neurons results in hypertrophy, increased migration, excitatory synaptogenesis, hyperexcitability, and epileptiform activity, the specific downstream signalling mediators of these pathologies remain to be fully elucidated. Using retroviral-mediated genetic manipulation of individual neurons within the Cre-lox system, we have analyzed pathway outputs in response to the manipulation of various genes using immunohistochemistry, confocal microscopy, and extensive morphological analyses, alongside whole-cell patch-clamp electrophysiology and 120-hour video-EEG monitoring for seizure assessment. Here, we demonstrate that signaling through AKT is necessary for the development of neuronal overgrowth, increased excitatory synapse formation, excessive migration, and hyperexcitability fueled by the loss of PTEN function. Notably, the concurrent deletion of Akt1 and Akt3 isoforms was sufficient to effectively rescue hypertrophic neuronal morphology and physiology. These findings establish AKT as the essential mediator through which PTEN deficiency manifests, providing a transformative therapeutic target to correct the morphological and functional defects central to PTEN-related neurodevelopmental disorders.

Keywords:  AKT; PKB; PTEN; autism; mTOR; seizure

DOI:  https://doi.org/10.1093/brain/awag098
Nat Rev Genet. 2026 Mar 09.

Gene regulatory networks: from correlative models to causal explanations.

Rory J Maizels, James Briscoe.

Gene regulatory networks (GRNs) explain how the genome controls cellular behaviour and tissue morphogenesis, serving to connect molecular mechanism to functional output. Single-cell technologies now provide descriptions of these networks with unprecedented detail, but this advance has also revealed gene regulatory systems that are too complex for our existing conceptual frameworks. GRNs, which should provide mechanistic explanations, are increasingly reduced to statistical correlations - 'hairballs' that fail to capture molecular causation. Here, we explore why this dilemma exists and propose a path forward. We argue that methods in 'representation learning' can be used to model GRNs, without needing to capture every molecular detail. For this framework, we advocate three linked principles: models must be inherently mechanistic, with structures grounded in cellular and evolutionary biology; molecular principles and constraints must be used to reduce the solution space for learning GRN models; and more sophisticated forms of experimental perturbation and synthetic biological engineering are needed to train models and test predictions. By reimagining GRNs through these principles, we can bridge the gap from data abundance to new conceptual understanding.

DOI: https://doi.org/10.1038/s41576-026-00939-1
Nat Rev Dis Primers. 2026 Mar 12. pii: 11. [Epub ahead of print]12(1):

Tuberous sclerosis complex.

Kellen Winden, E Martina Bebin, Shafali Jeste, Darcy A Krueger, Elahna Paul, Mustafa Sahin.

Tuberous sclerosis complex (TSC) is a rare genetic disease caused by heterozygous loss-of-function variants in TSC1 or TSC2. Patients present with benign tumours known as hamartomas in the brain, eyes, lungs, kidneys, heart and skin. Many hamartomas contain mosaic second hit variants in TSC1 or TSC2. The most disabling features of TSC include epilepsy and TSC-associated neuropsychiatric disorders (TAND) such as intellectual disability and autism spectrum disorder. Remarkable progress has been made both in understanding the pathogenesis of TSC and in its clinical management, largely due to the discovery of the link between TSC1 and TSC2 and the mechanistic target of rapamycin (mTOR) signalling pathway. TSC1 and TSC2 form a protein complex that inhibits mTOR. Naturally occurring inhibitors of mTOR (rapamycin) and its analogues, collectively known as rapalogues, have been used to test various hypotheses in preclinical models and are approved for the treatment of several manifestations of TSC. Approved drug treatments (rapalogues) exist for subependymal giant cell astrocytomas, renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, facial angiofibromas and refractory seizures. However, there is still an unmet need for effective treatment of TAND and refractory epilepsy, despite the available medical and surgical options.

DOI: https://doi.org/10.1038/s41572-026-00688-9
Theranostics. 2026 ;16(9): 4905-4922

Flow-induced Klf4-Akt signaling links EC cycling to mural cell defects in arterial-venous malformations.

Yanzhu Lin, Zohrah Hashemi, Qing Zhang, Yuxi Di, Tanmaya Behera, Johannes Gahn, Kuheli Banerjee, Fan Wu, Kornelia Andorfer, Mahak Singhal, Caroline Seebauer, Roxana Ola.

  Fluid shear stress (FSS) safeguards vascular homeostasis, coordinating endothelial cell (EC) behavior and endothelial - mural cell communication. Disrupted flow sensing driving excessive proliferation contribute to arterial-venous malformations (AVMs) in Hereditary Hemorrhagic Telangiectasia (HHT) vascular disorder. Yet, how flow-dependent cell cycle regulation intersects with mural cell remodeling in HHT remains unclear.
Methods: We used a combination between in vitro shear stress assays and in vivo analyses of multiple murine HHT models, including endothelial-specific loss of Activin-like kinase 1 (Alk1) or Smad4 and bone morphogenic factor 9/10 (BMP9/10) ligand blockade. Retinal vasculature and human nasal mucosal biopsies from HHT2 patients were examined for pathway conservation. Endothelial - mural cell crosstalk was evaluated using transwell and three-dimensional flow-dependent co-culture assays. Loss and gain of function studies were employed to define disease mechanisms.
Results: Across all studied murine HHT models and in HHT2 telangiectasias, AVM endothelium exhibited excessive flow-induced Krüpper-like 4 (KLF4) - Akt pathway activation, sustained EC proliferation, and abolition of FSS-mediated cyclin-dependent kinases 2/6 (CDK2/6) inhibition. The hyperproliferative state suppressed the expression of endothelial platelet-derived growth factor B (PDGFB) leading to pericyte loss, and and mural cell remodeling in AVMs. Restoration of endothelial quiescence via inhibition of KLF4, Akt or CDK4/6 rescued FSS-induced PDGFB expression. Pharmacological PDGFB induction with thalidomide restored mural cell coverage, and significantly reduced AVM burden in vivo.
Conclusion: Our study establishes EC cycle state as the upstream determinant of mural cell stability under pathological flow and provides the mechanistic reasoning for why distinct therapeutic strategies (e.g., CDK4/6 inhibition, Akt modulation, or thalidomide-induced PDGFB upregulation) converge on AVM stabilization.

Keywords:  AVM; BMP signaling.; HHT; cell cycle; mural cells; shear stress

DOI:  https://doi.org/10.7150/thno.121154
Nat Rev Dis Primers. 2026 Mar 12. pii: 12. [Epub ahead of print]12(1):

Tuberous sclerosis complex.

DOI: https://doi.org/10.1038/s41572-026-00692-z
Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2530194123

Pareto optimality reveals an atlas of cellular archetypes.

George Crowley, Uri Alon, Stephen R Quake.

  We sought to identify universal organizing principles behind phenotypic variation within cell types. Pareto optimality describes how trade-offs between optimal solutions account for variation, predicting that the boundary points of a data distribution reflect specialized functions. We hypothesized that transcriptomic variation was explained by Pareto optimality across all cell types. We then used the Tabula Sapiens Atlas of single-cell RNA sequencing across cell types and tissues in the human body to test this hypothesis and found that most cell types adhere to this theory. This enabled us to use this principled method to characterize the functions performed by each cell type. These phenotypes are derived from an unbiased approach and do not incorporate ideas from existing biological models or theories, and yet in many cases they recapitulate our understanding of the functions of major cell types. Ultimately, we conclude that multiobjective optimization broadly shapes the observed phenotypic variation within cell types. This finding enables us to write explicit representations of the low-dimensional manifolds on which transcriptomes of single cells reside. This can inform the design of the next generation of virtual cell language models, which aim to statistically learn low-dimensional transcriptomic manifolds.

Keywords:  biophysics; cell biology; computational biology

DOI:  https://doi.org/10.1073/pnas.2530194123
EMBO J. 2026 Mar 11.

Plakoglobin transmits tension across VE-cadherin for vascular leak formation and leukocyte diapedesis.

Neha Uttekar, Annette Artz, Vallari Ghanekar, Pragya Kaul, Jessica Heinrichs, Rebekka I Stegmeyer, Gizem Gülevin Takir, Astrid F Nottebaum, Dietmar Vestweber.

  VE-cadherin controls endothelial junction integrity, and thereby inflammation-induced vascular permeability and leukocyte extravasation. The adhesive function of VE-cadherin is influenced by its binding to β-catenin, which is linked by α-catenin to actin. Plakoglobin can replace β-catenin in such complexes, and both types of complexes co-exist in endothelial cells. Here, we have investigated whether β-catenin and plakoglobin differ in their relevance for controlling endothelial junctions. Based on gene silencing in vitro and conditional endothelium-specific gene inactivation in mice in vivo, we found that both leukocyte diapedesis through endothelium and induction of vascular permeability by inflammatory mediators depend on plakoglobin, but not β-catenin. Mechanistically, we demonstrated that plakoglobin is crucial for the generation of tension across VE-cadherin by transmigrating leukocytes and by inflammatory mediators, whereas β-catenin was dispensable in this context. Transgenic mice expressing a VE-cadherin tension sensor revealed that plakoglobin is essential in vivo for histamine-induced tension across VE-cadherin. Thus, plakoglobin, but not β-catenin, is needed for leukocyte diapedesis, the induction of vascular permeability, and the stimulation of mechanical tension across VE-cadherin.

Keywords:  Endothelial Junctions; Leukocyte Trafficking; Vascular Permeability

DOI:  https://doi.org/10.1038/s44318-026-00732-0
Cell Rep Methods. 2026 Mar 12. pii: S2667-2375(26)00029-9. [Epub ahead of print] 101329

Scalable nonparametric clustering with unified marker gene selection for single-cell RNA-seq data.

Chibuikem Nwizu, Madeline Hughes, Michelle L Ramseier, Andrew W Navia, Alex K Shalek, Nicolo Fusi, Srivatsan Raghavan, Peter S Winter, Ava P Amini, Lorin Crawford.

  Clustering is commonly used in single-cell RNA sequencing (scRNA-seq) to assess cellular heterogeneity, but standard methods often require user-specified heuristics and rely on post-selective differential expression analyses, which often lead to inflated false discovery rates. Here, we present NCLUSION: a nonparametric infinite mixture model that leverages Bayesian sparse priors to identify marker genes and cluster single-cell expression data simultaneously. NCLUSION uses a variational inference algorithm, which enables it to scale up to millions of cells. Through simulations and analyses of publicly available scRNA-seq studies, we demonstrate that NCLUSION (1) matches the performance of other state-of-the-art clustering techniques with significantly reduced runtime and (2) provides statistically robust and biologically relevant transcriptomic signatures for each of the clusters it identifies. Overall, NCLUSION represents a reliable hypothesis-generating tool for understanding patterns of expression variation present in single-cell populations.

Keywords:  CP: computational biology; CP: systems biology; clustering; machine learning; marker gene selection; nonparametric; variational inference

DOI:  https://doi.org/10.1016/j.crmeth.2026.101329
Eur J Paediatr Neurol. 2026 Mar 09. pii: S1090-3798(26)00013-9. [Epub ahead of print]61 36-41

Epilepsy in pediatric patients with PTEN hamartoma tumor syndrome: First step in recommendations for clinical management.

Ryan Jonker, Jolanda Schieving.

   BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal dominant syndrome caused by a mutation in the PTEN gene. Previous studies have suggested an association between PHTS and epilepsy, but the clinical characteristics of epilepsy in PHTS remain unknown.
OBJECTIVE: This study aims to expand knowledge of epilepsy in PHTS and provide insights into its clinical features.
METHODS: A retrospective observational study was conducted at the Radboud University Medical Center, including 149 patients with clinically or genetically confirmed PHTS. Electronic patient records were reviewed for baseline characteristics, epileptic features, therapeutic interventions, and neuroimaging results. A cumulative risk analysis for developing epilepsy was performed.
RESULTS: The prevalence of epilepsy among PHTS patients in this cohort was found to be 6%, with an estimated PHTS prevalence of 1:20 000 in the Netherlands. Autism spectrum disorder (ASD) was significantly associated with an increased risk of developing epilepsy (p = 0.002). A range of seizure semiologies was observed, with focal epilepsy being the most common, presenting as focal seizures with impaired awareness. EEG results predominantly showed (multi)focal discharges with variable localization. MRI abnormalities did not correlate with epileptic foci on EEG.
CONCLUSION: This study highlights the clinical characteristics of epilepsy in pediatric patients with PHTS. Follow-up should include monitoring for characteristics of focal epilepsy, with EEG utilized selectively when such episodes are observed, rather than as a routine screening measure. Treatment strategies should be individualized based on the patient's characteristics. In cases of epilepsy, MRI is recommended to identify potential structural malformations amenable to surgical intervention.

Keywords:  Autism spectrum disorder; Cowden syndrome; Epilepsy; PTEN hamartoma tumor syndrome; Pediatric

DOI:  https://doi.org/10.1016/j.ejpn.2026.03.004
Am J Physiol Heart Circ Physiol. 2026 Mar 09.

Guidelines for Evaluating Endothelial Function in Vascular Tissue.

Cameron G McCarthy, Christian Aalkjær, Pooneh Bagher, Andreas M Beyer, Ebbe Boedtkjer, Gisele F Bomfim, Jerome W Breslin, Ana M Briones, Jorge A Castorena-Gonzalez, Tiago J Costa, Zhiyu Dai, Ana P Davel, Scott Earley, Julie K Freed, Christopher Garland, Brant E Isakson, Thomas A Jepps, Joanna Kalucka, Boris Lavanderos, Ayako Makino, Charles E Norton, Steven S Segal, Wenbin Tan, Aaron J Trask, Calum Wilson, Scott D Zawieja, Camilla F Wenceslau.

  The endothelium plays a central role in maintaining vascular homeostasis by orchestrating vascular tone, inflammation, healing, permeability, and thrombosis. Assessing endothelial function in vascular tissue is essential for understanding the cellular and molecular mechanisms underlying cardiovascular physiology and pathology. Traditional approaches, such as wire and pressure myography, have been instrumental in defining endothelium-dependent responses and identifying key pharmacological targets. However, the complexity and heterogeneity of endothelial cells across vascular beds, and their dynamic phenotypic changes in health and disease, necessitate the incorporation of new investigative strategies. Emerging methodologies, including bulk and single-cell transcriptomics, proteomics, and advanced imaging, now provide unprecedented insights into endothelial cell diversity and function. A team of leading experts in the field, who collectively reached a consensus on the most widely used techniques to evaluate endothelial function, developed these guidelines. The document establishes best practices for assessing endothelial function, from endothelial cell cultures to isolated vascular tissues, integrating conventional functional assays with modern molecular approaches. By fostering methodological consistency and embracing innovation, our goal is to enhance rigor, reproducibility, understanding, and discovery in endothelial biology.

Keywords:  Endothelial Cells; Endothelium; Methods; Vasodilation; Vessels

DOI:  https://doi.org/10.1152/ajpheart.00656.2025