bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2026–08–23
twenty-two papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Integrated metabolomics data analysis to generate mechanistic hypotheses with MetaProViz.
  2. A chemigenetic endogenous Ras activity biosensor for live-cell pharmacology.
  3. Threonine 348 regulates the subcellular localization of PTEN.
  4. Sirolimus outperforms alpelisib in models of NRAS Q61R -driven vascular overgrowth.
  5. Spatial modulation of RAF by RAF/MEK glue enables full-dose combination with pan-RAF inhibitor and potent RAS-mutant tumor-selective MAPK and growth inhibition.
  6. Case Report: When benign overgrowth turns fatal in CLOVES syndrome: underestimated perioperative risk.
  7. Prevalence and clinical impact of PIK3CA and PTEN alterations from reflex genomic testing of newly diagnosed colorectal cancer: a population-based series.
  8. PIK3CA in-frame deletion-activated PI3K/AKT signaling pathway drives macrodactyly.
  9. Substrate-specific regulation of the mTORC1 pathway by G protein-coupled receptors.
  10. Semi-supervised Omics Factor Analysis (SOFA) disentangles known and latent sources of variation in multi-omic data.
  11. AKT1-dependent phosphorylation of PRMT5 prevents Siah1a-mediated CtBP1/2 ubiquitination to contribute to abdominal aortic aneurysm progression.
  12. Cancer cell plasticity: new insights from developmental programs.
  13. RASA1 deficiency aggravates the lesion burden of cerebral cavernous malformations via the Ras/Raf/MAPK pathway.
  14. A novel in vitro assay for quantifying endothelial cell and pericyte interactions.
  15. Development of a human iPSC and patient phenotyping resource for preclinical investigations of neurodevelopmental disorders.
  16. Pathogenesis and molecular mechanisms of mutant TIE2-driven venous malformation.
  17. Development of a universal imaging "phenome" using shape, appearance and motion (SAM) features and the SAM Phenotype Observation Tool (SPOT).
  18. Metabolic regulation of stem cell plasticity.
  19. Orbital Lymphatic Malformations Are Associated With Intracranial Vascular Anomalies.
  20. Fifteen challenges for generative AI applications to cell biology.
  21. Systematic functional genetic analysis of cell-substrate adhesion.
  22. PTEN-AKT2 regulates mixed lineage liver cancer development and sensitizes cancer cells to TGFβ treatment.
  1. Mol Syst Biol. 2026 Aug 17.
    Integrated metabolomics data analysis to generate mechanistic hypotheses with MetaProViz.
    Christina Schmidt, Jannik Franken, Denes Turei, Dimitrios Prymidis, Macabe Daley, Christian Frezza, Julio Saez-Rodriguez.
      The lack of standardised workflows and ambiguous metabolite annotations hampers metabolomics integration with prior knowledge, thus limiting the extraction of meaningful biological insights. We present MetaProViz (Metabolomics Processing, functional analysis and Visualization), an open-source Bioconductor R package for metabolomics data analysis that integrates prior knowledge to generate mechanistic hypotheses ( https://saezlab.github.io/MetaProViz/ ). MetaProViz operates on annotated intensity values and offers a flexible framework consisting of five modules: processing, differential analysis, prior knowledge integration, functional analysis and visualisation, applicable to intracellular and exometabolomics experiments. To improve functional analysis, we created the Metabolism Signature Database (MetSigDB), a collection of annotated metabolite sets. MetSigDB includes pathway-metabolite, metabolite-receptor, metabolite-transporter sets, and chemical class-metabolite sets. MetaProViz enables the conversion of gene sets to metabolite sets, metabolite identifier expansion and analyses mapping ambiguities. The MetaProViz functional analysis toolkit includes sample metadata analysis, enrichment analysis and biologically informed clustering. By applying MetaProViz to kidney cancer metabolomics data, we identified increased methionine usage in line with decreased methionine levels in tumour samples. In summary, MetaProViz facilitates and improves the analysis and interpretation of metabolomics data.
    DOI:  https://doi.org/10.1038/s44320-026-00231-8
  2. Nat Chem Biol. 2026 Aug 19.
    A chemigenetic endogenous Ras activity biosensor for live-cell pharmacology.
    Ryan Weeks, Daojia R Zhou, Michelle S Frei, Jin Zhang.
      Ras is a small GTPase that regulates cell growth and proliferation. Hyperactive Ras is prevalent in cancer and has been a therapeutic target for decades. Many lines of evidence have demonstrated that Ras signals from the plasma membrane as well as noncanonical compartments such as the Golgi, making live-cell biosensors for tracking the spatiotemporal dynamics of Ras activity a valuable approach for Ras studies. However, current biosensors are limited in their quantitative capacity for measuring endogenous Ras activity. Here we introduce a chemigenetic biosensor design, making use of circularly permuted HaloTag labeled with the fluorophore JF635, for detecting endogenous Ras activity. This HaloTag-based Ras Activity Reporter (HaloRasAR) revealed the spatiotemporal dynamics of Ras activity downstream of either growth factor signaling or protein kinase C activation. In addition, live-cell characterization of a Ras(G12C) inhibitor and a Ras GEF inhibitor revealed subcellular-specific inhibition profiles. HaloRasAR represents a major advance in spatiotemporal interrogation of Ras signaling and live-cell pharmacology.
    DOI:  https://doi.org/10.1038/s41589-026-02276-0
  3. FEBS Open Bio. 2026 Aug 19.
    Threonine 348 regulates the subcellular localization of PTEN.
    Takashi Kato, Suzu Tanaka, Miyu Ohashi.
      The tumor suppressor PTEN (phosphatase and tensin homolog) dephosphorylates PIP3 (phosphatidylinositol (3,4,5)-trisphosphate) at the plasma membrane and protects genomic integrity in the nucleus; thus, regulation of PTEN subcellular localization is crucial. Previous studies have shown that the PTEN350 fragment is markedly enriched in the nucleus, a feature not explained by the N-terminal nuclear localization signal. In this study, we generated PTEN fragments of various lengths and identified PTEN348 (residues 1-348), which showed prominent nuclear localization. Furthermore, the replacement of threonine 348 (Thr348) with other amino acids reduced the nuclear localization of the PTEN348 and PTEN350 fragments. Moreover, we found that PTENA4 and PTENK13R,A4 localized predominantly to the nucleus and plasma membrane, respectively, and that substitution of Thr348 with aspartic acid resulted in cytoplasmic localization in both mutants. Collectively, these results indicate that Thr348 is a key contributor to the regulation of PTEN subcellular localization.
    Keywords:  C2 domain; PTEN; nucleus; plasma membrane; subcellular localization; threonine 348
    DOI:  https://doi.org/10.1002/2211-5463.70328
  4. Blood Vessel Thromb Hemost. 2026 Aug;3(3): 100192
    Sirolimus outperforms alpelisib in models of NRAS Q61R -driven vascular overgrowth.
    Svatava Merkle, Sara Alharbi, Patricia Pastura, C Griffin McDaniel, Timothy D Le Cras.
      The somatic neuroblastoma rat sarcoma virus gene p.Q61R mutation (NRAS Q61R ) occurs in patients with kaposiform lymphangiomatosis (KLA), a highly morbid and potentially fatal complex lymphatic disease. First-line therapy for KLA is mammalian target of rapamycin (mTOR) inhibitor sirolimus, although partial responses and disease progression can still occur. Alpelisib is a US Food and Drug Administration-approved p110α catalytic subunit of phosphoinositide 3-kinase α (PIK3CA) inhibitor for severe manifestations of PIK3CA-related overgrowth spectrum, and inhibits upstream of sirolimus in the phosphoinositide 3-kinase (PI3K)-mTOR pathway. Recent clinical interest in expanding the indications for alpelisib prompted this preclinical study, which aimed to determine whether alpelisib could serve as a more effective treatment for patients with KLA than sirolimus, given its upstream activity in the PI3K-mTOR signaling pathway. We compared the efficacy of sirolimus and alpelisib using NRAS Q61R endothelial cell models through in vitro assessments of pathway inhibition, cell proliferation, and migration, as well as in vivo xenograft studies. Sirolimus, at picomolar doses, outperformed alpelisib administered at micromolar concentrations across all in vitro assays and at lower doses in vivo. The use of alpelisib to treat patients with endothelial NRAS Q61R mutation may not offer any advantages over sirolimus.
    DOI:  https://doi.org/10.1016/j.bvth.2026.100192
  5. bioRxiv. 2026 Jul 27. pii: 2026.07.24.740654. [Epub ahead of print]
    Spatial modulation of RAF by RAF/MEK glue enables full-dose combination with pan-RAF inhibitor and potent RAS-mutant tumor-selective MAPK and growth inhibition.
    Ana Orive-Ramos, Bijaya Gaire, Christos Adamopoulos, Beau Baars, Mathieu Desaunay, Ziyue Kou, Evangelia Matenoglou, Silvia Coma, Nayeli Gutiérrez-Trejo, Kevin Mohammed, Stuart A Aaronson, Jian Jin, Tiphaine C Martin, Ernesto Guccione, Evripidis Gavathiotis, Jonathan A Pachter, Poulikos I Poulikakos.
      The clinical benefit of MAPK-targeted therapies depends on greater pathway inhibition in tumors than normal tissues. Although pan-RAF inhibitors are active in RAS-mutant cancers, combining them with MEK inhibitors requires dose reductions due to toxicity, limiting efficacy. We show the toxicity results from MEK inhibitor-mediated feedback relief, which promotes RAF activation and pan-RAF inhibitor engagement in normal cells, narrowing the therapeutic index. We further demonstrate that MEK is exclusively cytosolic, and RAF/MEK glues overcome this limitation through spatial trapping. By stabilizing cytosolic RAF-MEK complexes, RAF/MEK glues prevent feedback-driven RAF activation in normal cells while maintaining inhibition of oncogenic RAF signaling in RAS-mutant tumors, where RAF is constitutively activated at the plasma membrane. Consequently, this enables full-dose combination with pan-RAF inhibitors, resulting in deeper MAPK suppression and robust tumor regressions in RAS-mutant models. Thus, by spatially controlling wild-type effectors, drug-induced proximity can be harnessed to increase tumor selectivity of pathway-targeted therapies.
    Significance: MAPK-targeted therapies rarely achieve durable responses in RAS-mutant cancers due to dose-limiting toxicities. We show that RAF/MEK glues, by spatially trapping RAF, can be combined with pan-RAF inhibitors at full dose, yielding tumor-selective MAPK inhibition and tumor regressions in RAS-mutant models. Thus, drug-induced proximity can be exploited for tumor-selective therapy.
    DOI:  https://doi.org/10.64898/2026.07.24.740654
  6. Front Med (Lausanne). 2026 ;13 1883591
    Case Report: When benign overgrowth turns fatal in CLOVES syndrome: underestimated perioperative risk.
    Yuheng Cui, Yang Liu, Guoliang Shi, Ning Wang, Yueqiao Xu, Xin Qu, Hao Zhao, Meng Qi, Weitao Cheng, Wenjin Chen, Lidan Jiang, Tao Liu, Rongcai Jiang.
      CLOVES syndrome is driven by somatic activating PIK3CA mutations that constitutively activate the PI3K-AKT-mTOR pathway, resulting in segmental overgrowth and complex vascular malformations. Emerging evidence suggests these vascular lesions are biologically active and may pre-dispose to localized intravascular coagulation and thrombosis. We report a 21-year-old man with genetically confirmed CLOVES syndrome who developed concurrent consumptive coagulopathy and hypercoagulability. Post-operatively, he experienced both hemorrhagic and thromboembolic complications, culminating in fatal cardiac arrest. This case highlights a fragile perioperative hemostatic balance in CLOVES syndrome, underscoring the need for careful risk stratification and multidisciplinary management.
    Keywords:  CLOVES syndrome; coagulation abnormalities; multidisciplinary management; perioperative risk; vascular malformations
    DOI:  https://doi.org/10.3389/fmed.2026.1883591
  7. Front Oncol. 2026 ;16 1888745
    Prevalence and clinical impact of PIK3CA and PTEN alterations from reflex genomic testing of newly diagnosed colorectal cancer: a population-based series.
    Laura Kerrin, Osamah Al Haddad, Ellen Reid, John-Joe O'Neill, Lauren McConnell, Anthony Abladey, Paul J Kelly, Jacqueline A James, Catherine Davidson, Jack Lee, Catherine Hanna, Maurice B Loughrey, Mark A Catherwood, Vicky M Coyle.
       Background: Results from the Adjuvant Low dose Aspirin in Colorectal Cancer (ALASCCA) clinical trial demonstrate a survival benefit associated with aspirin use in patients with non-metastatic colorectal cancer (CRC) harbouring phosphoinositide 3-kinase (PI3K) pathway alterations. Identification of patients in routine clinical care is required for implementation of this therapeutic approach. A real-world analysis of reflex diagnostic testing was performed to assess prevalence of PI3KCA and PTEN gene alterations and potential clinical impact.
    Methods: Next generation sequencing panel testing of all newly diagnosed CRC as part of a Lynch screening service began in the Northern Ireland Cancer Network in 2022. Profiling, using a capture hybridisation assay and custom Small Cancer Panel covers all coding regions of PTEN and PIK3CA with a limit of detection of 4% variant allele frequency (VAF).
    Results: 1516 CRC patients underwent genomic profiling at the point of diagnosis from January 2024-March 2025. Across all CRC stages, 170 patients (11.2%) had tumours harbouring PIK3CA mutations with the majority occurring in exon 9 and 20. A further 51 of 1516 tumours (3.4%) demonstrated PTEN mutations. Of 221 patients with PIK3CA/PTEN alterations, 174 (79%) had non-metastatic CRC, of whom 6 (3.4%) had an absolute contraindication to aspirin use. Overall, 168 (11.1%) of 1516 patients in this cohort were therefore identified by this reflex testing pathway as potentially eligible for treatment.
    Conclusions: Prevalence of PIK3CA and PTEN alterations in this series (14.6%) was lower than in the ALASCCA trial (37%) but these results represent a real-world rather than a highly selected trial population. Regardless, our findings support implementing testing for use of a safe, inexpensive repurposed drug and underscore the importance of upfront testing for timely treatment decision-making and implementation of trial findings into routine practice.
    Keywords:  PIK3CA; PTEN; colorectal cancer; non-metastatic; population series
    DOI:  https://doi.org/10.3389/fonc.2026.1888745
  8. Yi Chuan. 2026 Aug;48(8): 796-806
    PIK3CA in-frame deletion-activated PI3K/AKT signaling pathway drives macrodactyly.
    Jing-Heng Wu, Shan-Lin Chen, Yun-Hao Xue, Peng-Cheng Li, Meng-Meng Tian.
      Macrodactyly is a congenital abnormality characterized by overgrowth of single or multiple digits, frequently accompanied by pathological changes in bone, soft tissue, and nerve tissue, and is caused mostly by somatic variants. Previous studies have demonstrated that macrodactyly is predominantly caused by pathogenic variants in the PIK3CA gene, yet the underlying molecular mechanism remains unclear. In this study, we analyzed 13 patients clinically diagnosed with isolated macrodactyly. Through whole-exome and Sanger sequencing, we identified one pediatric patient carrying a novel mosaic de novo in-frame deletion mutation (c.307_312del/p.Glu103_Pro104del) in the PIK3CA gene, which was not detected in either parent. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, we classified this mutation as a variant of uncertain significance (PM4+PM2_Supporting+PM6_Supporting). Protein structure prediction analysis indicated that this in-frame deletion altered the protein's local conformation and surface electrostatic potential. Furthermore, the wild-type and mutant expression vectors were constructed, including the well-established pathogenic mutation c.353G>A/p.Gly118Asp in PIK3CA gene as a control. We transfected these vectors into HEK293T cells for functional analyses, respectively. The results showed that although this mutation did not significantly affect PIK3CA mRNA or protein expression levels, it promoted the phosphorylation of downstream AKT protein at both Thr308 and Ser473. Therefore, the mutation may express the localized overgrowth phenotype by activating the PI3K/AKT signaling pathway. This study not only expands the genetic variant spectrum of macrodactyly, but also further clarifies the role of the PI3K/AKT pathway in the PIK3CA-related overgrowth.
    Keywords:  PI3K-AKT; PIK3CA ; in-frame deletion; macrodactyly; phosphorylation
    DOI:  https://doi.org/10.16288/j.yczz.25-340
  9. Biochem J. 2026 Aug 19. pii: BCJ20260165. [Epub ahead of print]
    Substrate-specific regulation of the mTORC1 pathway by G protein-coupled receptors.
    Samuel J Atkinson, Florentina Negoita, Yuichiro Ioi, William Vincent Ritchie, Kyle Thompson, Max Gardner, Peter T Ashdown, Kristina Hellberg, Terunao Takahara, Kei Sakamoto, Dawn Thompson, James N Hislop, Riko Hatakeyama.
      The mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) orchestrates cell growth and metabolism in response to diverse extracellular and intracellular cues. mTORC1 phosphorylates a broad range of substrates, each of which plays important physiological roles. Emerging evidence suggests that mTORC1 can respond to upstream signals in a nuanced manner, enabling differential regulation of individual substrates and, consequently, specific downstream biological processes. Phosphorylation of non-canonical mTORC1 substrates, such as the lysosome biogenesis regulator transcription factor EB (TFEB), can be regulated independently of phosphorylation of canonical substrates. However, the nature of signals that determine the signaling selectivity of mTORC1 remains incompletely understood. Here, we studied mTORC1 regulation by G protein-coupled receptors (GPCRs). We found that phosphorylation of TFEB responds to GPCRs differently, compared to canonical mTORC1 substrates controlling protein synthesis such as S6K1 and 4EBP1. In particular, the muscarinic acetylcholine receptor M5 (M5R) promoted phosphorylation of S6K1 and 4EBP1, while triggering TFEB dephosphorylation. Consequently, M5R stimulated protein synthesis without inhibiting lysosome biogenesis. mTORC1 can thus separately regulate anabolic and catabolic processes under the control of M5R. This study highlights the importance of reassessing the effects of GPCRs on mTORC1 by concurrently monitoring individual substrates, a critical consideration to be made when evaluating GPCR ligands as therapeutic agents targeting the mTORC1 pathway.
    Keywords:  G protein-coupled receptor (GPCR); mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1); muscarinic acetylcholine receptor M5 (M5R)
    DOI:  https://doi.org/10.1042/BCJ20260165
  10. Nat Commun. 2026 Aug 20. pii: 8725. [Epub ahead of print]17(1):
    Semi-supervised Omics Factor Analysis (SOFA) disentangles known and latent sources of variation in multi-omic data.
    Tümay Capraz, Harald Vöhringer, Klaus Sebastian Augusto Kruger Serrano, Ricardo Omar Ramirez Flores, Julio Saez-Rodriguez, Wolfgang Huber.
      A fundamental design pattern in biomolecular studies is to assay the same set of samples (organisms, tissue biopsies, or individual cells) by multiple different 'omics assays. Group Factor Analysis (GFA) and its adaptation to high-dimensional settings, Multi-Omics Factor Analysis (MOFA), are widely used as a first-line approach to analyze such data and are effective in detecting patterns of correlation, organize them into so-called latent factors, and identify common and assay-specific factors. However, in many applications, a subset of the found factors just rediscovers already known covariates (e.g., disease subtypes, environmental covariates) while others may represent genuine novelty.Here, we present Semi-supervised Omics Factor Analysis (SOFA), a method that incorporates known covariates into the model upfront and focuses the factor discovery on novel sources of variation. We show SOFA's effectiveness for discovering novel patterns by applying it to cancer, brain development and heart failure multi-omic data sets.
    DOI:  https://doi.org/10.1038/s41467-026-74694-6
  11. Life Sci. 2026 Aug 20. pii: S0024-3205(26)00454-6. [Epub ahead of print] 124645
    AKT1-dependent phosphorylation of PRMT5 prevents Siah1a-mediated CtBP1/2 ubiquitination to contribute to abdominal aortic aneurysm progression.
    Lei Bai, Lijuan Ge, Bo Jiang, Yanyan Song.
       AIMS: Abdominal aortic aneurysm (AAA) is a progressive vascular disease characterized by chronic inflammation and extracellular matrix (ECM) degradation. Although C-terminal binding protein 1 and 2 (CtBP1/2)-mediated transcriptional activation has been implicated in AAA progression, the upstream mechanisms regulating CtBP stability remain unclear.
    MATERIALS AND METHODS: We combined tandem mass tag (TMT)-based proteomics, biochemical assays, and functional analyses in calcium chloride (CaCl₂)- and elastase-induced AAA mouse models and in TNF-α-stimulated primary aortic endothelial cells. Immunoprecipitation, mass spectrometry, mutagenesis, in vitro kinase and methylation assays, and preventive inhibition experiments were used to define the regulatory pathway controlling CtBP1/2.
    KEY FINDINGS: Proteomic analyses revealed activation of the phosphatidylinositol 3-kinase catalytic subunit alpha (PI3Kα)-protein kinase B (AKT1) pathway accompanied by upregulation of PRMT5 (protein arginine methyltransferase 5) in AAA tissues. AKT1 directly phosphorylated PRMT5 at Thr634, which enhanced PRMT5-mediated arginine methylation of CtBP1 and CtBP2 at R283 and R289, respectively. This methylation prevented Siah1a (seven in absentia homolog 1a)-dependent ubiquitination and proteasomal degradation of CtBP1/2, thereby stabilizing the CtBP1/2 complex. Stabilized CtBP1/2 promoted the expression of matrix metalloproteinases and proinflammatory cytokines, reinforcing ECM destruction and vascular inflammation. Conversely, PRMT5 deficiency enhanced CtBP1/2 destabilization. In vivo, preventive inhibition of PI3Kα, AKT1, or PRMT5 markedly attenuated inflammatory cytokine production, aneurysmal dilation, and histopathological injury during AAA development.
    SIGNIFICANCE: These findings identify an AKT1-PRMT5-Siah1a-CtBP1/2 signaling axis that links phosphorylation, arginine methylation, and ubiquitin-mediated degradation during AAA development, suggesting that modulation of this pathway may provide a potential preventive strategy for experimental AAA.
    Keywords:  AKT1; Abdominal aortic aneurysm; CtBP1/2; Extracellular matrix; PRMT5; Siah1a
    DOI:  https://doi.org/10.1016/j.lfs.2026.124645
  12. Trends Cancer. 2026 Aug 21. pii: S2405-8033(26)00165-2. [Epub ahead of print]
    Cancer cell plasticity: new insights from developmental programs.
    Vincent J Guen, Robert A Weinberg.
      Tumors represent a heterogeneous set of neoplastic diseases, each composed of an intricate network of cancer cells residing in multiple alternative phenotypic states. Transitions between these phenotypic states, often termed 'phenotypic plasticity', enable them to execute specific steps in tumor progression and to develop therapeutic resistance. The phenotypic plasticity of tumor cells is mediated, in part, by cellular processes that orchestrate normal embryonic development and are hijacked by tumors. In this review, we discuss the contributions of these developmental programs to cancer cell phenotypic plasticity. We focus on epithelial-mesenchymal transition and ciliogenesis programs and discuss new insights into the mechanistic roles of these cellular processes in cancer progression and response to treatment.
    Keywords:  cancer cell plasticity; ciliogenesis; epithelial–mesenchymal transition; intratumor heterogeneity
    DOI:  https://doi.org/10.1016/j.trecan.2026.07.009
  13. iScience. 2026 Aug 21. 29(8): 117126
    RASA1 deficiency aggravates the lesion burden of cerebral cavernous malformations via the Ras/Raf/MAPK pathway.
    Yuwen Wang, Ziyu Xiong, Qile Ye, Ying Li, Dongdong Zhang, Wenzhong Du, Cong Yan, Guofu Li, Zifeng Dai, Jingwei Li, Yongqing Ye, Chunyang Men, Qianpeng Duan, Rui Bi, Jiayu Song, Silengtu Hu, Xia Zhao, Changbin Shi.
      Cerebral cavernous malformations (CCMs) are cerebrovascular lesions that can be influenced by genetic alterations affecting endothelial signaling. Here, we investigated how RASA1 deficiency modifies CCM progression using bioinformatic analyses, hCMEC/D3 endothelial knockdown and rescue models, Seahorse metabolic profiling, Ras-GTP pull-down assays, and a PDCD10-deficient mouse model with endothelial Rasa1 knockdown. RASA1 deficiency promoted endothelial proliferation, reduced ZO-1 expression, shifted energy metabolism from oxidative phosphorylation toward glycolysis, and activated Ras/Raf/MAPK signaling. RASA1 rescue or pharmacological Ras inhibition with RMC-7977 partially reversed these abnormalities in vitro, and RMC-7977 reduced lesion severity and Ras/Raf/MAPK activation in vivo. These findings provide mechanistic evidence that RASA1 deficiency aggravates CCM-like pathology through Ras/Raf/MAPK pathway activation and support further investigation of Ras-targeted strategies for genetically defined CCM subtypes.
    Keywords:  RASA1; Ras/Raf/MAPK pathway; metabolic reprogramming; sporadic cerebral cavernous malformations; vascular endothelial proliferation
    DOI:  https://doi.org/10.1016/j.isci.2026.117126
  14. bioRxiv. 2026 Aug 04. pii: 2026.08.03.742618. [Epub ahead of print]
    A novel in vitro assay for quantifying endothelial cell and pericyte interactions.
    David J Csordas, Lily C Cucuzzella, John S Kim, Shayn M Peirce.
       Objective: Structural adaptations of capillary networks, through angiogenesis, arterialization, and regression, are implicated in many diseases, and gaining a better understanding of the cell-cell interactions that underpin these adaptations may lead to novel therapeutic discoveries for disease management. Endothelial cells and pericytes are the two cell types that comprise capillary networks. Experimental model systems have been developed to study the dynamic interactions between endothelial cells and pericytes, providing valuable insights into capillary development, cell-to-cell communication, and responses to growth factors and therapeutic agents.
    Methods: In this study, we present a novel and simple co-culture system that uses commercially available primary human endothelial cells and pericytes, does not require microfluidic perfusion, and allows simultaneous observation of cell morphologies and interactions over time in 60 samples, enabling high-throughput analysis of multiple culture conditions with replicates.
    Results: Image analysis pipelines were created to quantify microvascular adaptations, including one to measure colocalization between endothelial cells and pericytes, capturing dynamic coupling and uncoupling associated with capillary stability, angiogenesis, and regression. We validated the ability of our co-culture system to reproducibly represent the effects of fibrotic and angiogenic activation signals, including an FDA-approved drug, on endothelial cells, pericytes, and their coupling.
    Conclusion: This novel, high-throughput microvascular screening assay enables quantification of microvascular dynamics in response to disease-relevant stimuli and therapeutics in a repeatable, real-time manner.
    DOI:  https://doi.org/10.64898/2026.08.03.742618
  15. Stem Cell Res. 2026 Aug 06. pii: S1873-5061(26)00169-8. [Epub ahead of print]95 104073
    Development of a human iPSC and patient phenotyping resource for preclinical investigations of neurodevelopmental disorders.
    Cidi Chen, Wardiya Afshar-Saber, Isabela Iglesias, Kristina Kim, Becca Lewis, Gayathri Srinivasan, Celeste Chen, Remi Hirsh, Ryan Guardado, Taryn Polanco, Amanda Swanson, Erika Norabuena, Dosh Whye, Ashish Jain, Chunhui Cai, Liang Sun, Maya Chopra, Ivy Chen, Grazia Iannello, Brian Rozumny, Ellen Hanson, Mustafa Sahin, Elizabeth D Buttermore.
      In this manuscript, we report the development of a comprehensive resource designed to harness the transformative potential of patient-derived induced pluripotent stem cells (iPSCs) to advance the study of neurodevelopmental disorders (NDDs). Using CRISPR-Cas-mediated genome editing, the Human Neuron Core generated a repository comprising 29 isogenic iPSC pairs, two sex-matched parental control iPSC pairs, and one unmatched patient line representing six monogenic NDDs: Tuberous Sclerosis Complex, PTEN Hamartoma Tumor Syndrome, KCNQ2 Developmental and Epileptic Encephalopathy, FOXG1 Syndrome, Phelan-McDermid Syndrome, and SETBP1 Haploinsufficiency Disorder. In parallel, detailed clinical phenotyping data were collected to enable comparison of cellular phenotypes with clinical severity in future studies. This integrated collection of genetically defined iPSC lines and associated clinical data provides a powerful platform for investigating disease mechanisms and advancing iPSC-based drug discovery for NDDs.
    Keywords:  CRISPR-CAS9; Gene editing; Human induced pluripotent stem cells; Neurodevelopmental disorders
    DOI:  https://doi.org/10.1016/j.scr.2026.104073
  16. Angiogenesis. 2026 Aug 20. pii: 62. [Epub ahead of print]29(4):
    Pathogenesis and molecular mechanisms of mutant TIE2-driven venous malformation.
    Lindsay J Bischoff, Elisa Boscolo.
      Venous malformation (VM) is the most common subtype of vascular malformation. Due to the chronic nature of this disorder, VM patients face significant morbidity and complications throughout their lives. Current therapeutic options can be limited, but recent advances in understanding the cellular and molecular mechanisms that underly VM pathogenesis provide hope for the discovery of more effective targeted therapies. These advances arise from a greater understanding of the cellular effects of VM-causative mutations, which has been aided by the development of more advanced and physiologically relevant model systems. In this review, we begin by providing a brief overview of the clinical characteristics and genetic driver mutations of the most common subtypes of all vascular anomalies (including vascular tumors and vascular malformations), providing context for our more detailed discussion of these aspects of VM. We further summarize the current treatment options available for VM patients and the advancements that have been made in the use of targeted therapies for these patients. We further discuss recent advances in the development of model systems that can be used to study VM pathogenesis. Finally, we focus this review on the mechanisms that are downstream of mutant TIE2, discussing structural features of the receptor, TIE2 signaling pathways, and its roles in vascular physiology and VM pathology.
    Keywords:  PIK3CA; TIE2; Vascular anomaly; Venous malformation
    DOI:  https://doi.org/10.1007/s10456-026-10088-y
  17. Nat Commun. 2026 Aug 17. pii: 8409. [Epub ahead of print]17(1):
    Development of a universal imaging "phenome" using shape, appearance and motion (SAM) features and the SAM Phenotype Observation Tool (SPOT).
    Felix Y Zhou, Adam Norton-Steele, Lewis Marsh, Helen M Byrne, Heather A Harrington, Xin Lu.
      Cells are plastic, highly heterogeneous and change over time. High-content timelapse imaging promises to reveal dynamic cell behaviors, enabling more accurate identification of cell state and cell fate prediction for biological hypothesis generation and perturbation screens. To empower live-cell imaging based screening, we report the development of (1) a Shape, Appearance, Motion (SAM) "phenome"; a universal set of 2185 image-derived features that act as a image-"transcriptome" to comprehensively quantify an object's instantaneous phenotype; (2) the SAM-Phenotype-Observation-Tool (SPOT), for image-"sequencing" analysis of phenomes. We validate the effectiveness of unbiased SAM-SPOT workflow on publicly available computer vision and 2D single cell imaging datasets. Importantly, we demonstrate that SAM-phenome outperforms features generated by deep learning AI models trained on >1 million fixed single cell and >5000 single cell video frames, respectively. SAM-phenome and SPOT deliver high-throughput, object-treatment-agnostic, comprehensive screening readouts of dynamics, promising to advance novel molecular target discovery and new medicine development.
    DOI:  https://doi.org/10.1038/s41467-026-75505-8
  18. Curr Opin Genet Dev. 2026 Aug 15. pii: S0959-437X(26)00097-3. [Epub ahead of print]100 102530
    Metabolic regulation of stem cell plasticity.
    Emilia Kuuluvainen, Swetha Gopalakrishnan, Pekka Katajisto.
      Stem cells must accurately balance self-renewal with the generation of specialized cells that each adopt the type of metabolism facilitating their specific function. However, recent advances demonstrate that metabolism can regulate decisions between self-renewal and differentiation, in addition to being a downstream outcome of transcriptional programs of differentiation. Here we discuss how metabolism influences mammalian stem cells, focusing on the conundrum of how cell fate determination can be accurately controlled if the endpoint product - the specialized cellular metabolism - can influence the process. We propose that most stem cells are guided by intrinsic and extrinsic metabolic cues, creating dynamic metabolic states that may differ in lineage preferences and activity but do not pose a deterministic impact on stem cell potency. Such metabolic plasticity safeguards tissue maintenance and regeneration from modest metabolic fluctuations, but disruptions beyond the limits of metabolic plasticity can impair stem cell function and fate potential.
    DOI:  https://doi.org/10.1016/j.gde.2026.102530
  19. Laryngoscope. 2026 Aug 19.
    Orbital Lymphatic Malformations Are Associated With Intracranial Vascular Anomalies.
    Kelsey A Loy, Jennifer Siu, Clare Richardson, J Nathaniel Perkins, Kaitlyn Zenner, Kevin Koo, Francisco Perez, James Bennett, Randall Bly, Danial K Hallam, Amy Geddis, Jonathan A Perkins.
       OBJECTIVES: Orbital lymphatic malformations (OLMs) are a rare type of lymphatic malformation involving the soft tissues within the bony orbit. OLMs present specific treatment challenges and cause significant morbidity. The contribution of pathologic genetic variants and potential association of intracranial vascular anomalies with OLMs has yet to be described. We hypothesized that (1) OLMs are indicators of underlying cerebrofacial venous metameric syndrome (CVMS) and are associated with intracranial vascular anomalies, and (2) OLMs are caused by PIK3CA variants and are candidates for targeted medical therapy.
    METHODS: Retrospective case review was performed for patients with OLMs treated at a single institution from 2000 to 2025. Diagnosis of CVMS was made via magnetic resonance imaging (MRI) based on established criteria of segmental distribution of ocular, facial, and cerebral vascular malformations. Symptoms, MRI and genetic findings, and management are described.
    RESULTS: Seven of 412 patients with head and neck lymphatic malformations had OLM. Common symptoms included eye swelling (n = 7), ptosis (n = 3), and headache (n = 5). All patients were diagnosed with CVMS on MRI. All patients underwent surgical resection and were candidates for targeted medical therapy after tissue-based DNA sequencing revealed "hotspot" PIK3CA variants p.E542K (n = 4) and p.H1047R (n = 3). Five patients were started on alpelisib, resulting in symptom improvement at 6 months of treatment.
    CONCLUSION: OLMs were associated with intracranial vascular anomalies, meeting radiographic criteria for CVMS. All patients had "hotspot" PIK3CA variants on tissue-based genetic testing. Screening for intracranial vascular anomalies and targeted medical therapy with PI3K/AKT/mTOR pathway inhibitors should be considered in OLM management.
    LEVEL OF EVIDENCE: 3:
    Keywords:  cerebrofacial venous metameric syndrome; orbital lymphatic malformations; targeted medical therapy; vascular anomalies
    DOI:  https://doi.org/10.1002/lary.70826
  20. Cell. 2026 Aug 17. pii: S0092-8674(26)00802-0. [Epub ahead of print]
    Fifteen challenges for generative AI applications to cell biology.
    Leo Dupire, Aly A Khan, Theofanis Karaletsos, Shana Kelley, Emma Lundberg, Jian Ma, Evan Paull, Stephen R Quake, Raul Rabadan, Cassius Rowan, Peter Sims, Sohail Tavazoie, John S Tsang, Mingxuan Zhang, Andrea Califano.
      Generative AI (Gen-AI) has shown a remarkable impact in several biological research areas, from protein folding and de novo design to pathogenic mutation prediction. However, it remains unclear whether these molecular-level successes can translate to cellular and multicellular insights relevant to fields ranging from immunology to cancer and neurodegeneration. This arises from the intricate nature of the molecular mechanisms that determine cellular and organismal behavior, the lack of sufficient training data, and the multicellular nature of most pathophysiologic phenotypes. Novel Gen-AI frameworks are likely needed to integrate prior biological knowledge, such as molecular interaction networks, as well as guiding principles focusing the community's attention on solving biologically and translationally relevant problems. Drawing inspiration from Hilbert's list of 23 mathematical problems that have focused the mathematical community's attention for more than a century, we propose fifteen grand AI challenges to focus the biomedical community's attention on critically relevant questions, most of which still lack effective predictive methodologies.
    Keywords:  generative AI; large language models; predictive biology; systems biology; systems immunology
    DOI:  https://doi.org/10.1016/j.cell.2026.07.004
  21. bioRxiv. 2026 Jul 27. pii: 2026.07.24.740569. [Epub ahead of print]
    Systematic functional genetic analysis of cell-substrate adhesion.
    Kaitlyn Manzer, Kuan-Chung Su, Matteo Di Bernardo, Heather R Keys, Russell Walton, Brittania Moodie, Bingbing Yuan, Paul C Blainey, Iain Cheeseman.
      Cellular adhesion is critical for tissue organization and integrity, but the full complement of proteins required for proper adhesion remains unresolved. Here, we define the requirements for cell-substrate adhesion in cultured human cells using orthogonal, large-scale functional genetic approaches. Using mechanical assays to test the maintenance ("shake-off") or formation of adhesion and parallel large-scale assays of cell morphology, we identify dozens of gene targets with roles in adhesion. Our analyses reveal dynamic requirements for adhesion across timepoints and cell lines. We additionally conduct targeted downstream mechanistic analyses to resolve the molecular basis for altered adhesion. Collectively, we identify established and uncharacterized regulators of adhesion, including genes involved in mitosis, focal adhesions, actin regulation, and membrane trafficking. Unexpectedly, we find that cells that fail cytokinesis display impaired adhesion, with strongly altered actin organization and nuclear dynamics. Together, this work provides a comprehensive view of the genetic requirements for cell-substrate adhesion.
    DOI:  https://doi.org/10.64898/2026.07.24.740569
  22. Oncogene. 2026 Aug 20.
    PTEN-AKT2 regulates mixed lineage liver cancer development and sensitizes cancer cells to TGFβ treatment.
    Qi Tang, Ielyzaveta Slarve, Jingyu Chen, Ni Zeng, Yiwei Gu, Lina He, Shunan Hu, Diala Alhousari, Zifei Xu, Brittney Hua, Guo Zhang, Phillip Nguyen, Mario Alba, Ajay Bharadwaj, Jihyeon Lee, Simion Kreimer, Jian Xu, Baoan Ji, Shelly C Lu, Jennifer Van Eyk, Shefali Chopra, Gary Kanel, Liyun Yuan, Bangyan L Stiles.
      Primary liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), arise from the neoplastic transformation of hepatocytes and cholangiocytes, respectively. Loss or downregulation of PTEN, a tumor suppressor negatively regulating the PI3K/AKT pathway, is frequently observed in CCA and HCC. Notably, PTEN mutations are observed at nearly twice the frequency in combined CCA-HCC tumors than either HCC or CCA alone. Using lineage-specific liver-targeted PTEN-deficient mouse models, we demonstrate that PTEN loss drives cellular dedifferentiation and tumorigenesis, a process that is critically dependent on AKT2. Mechanistically, PTEN deficiency induces activation of NOTCH and upregulation of transcriptional factor SOX9, which plays a central role in tumor cell transformation. In parallel, PTEN loss increases SMAD4 expression and sensitizes the tumor cells to TGFβ signaling, with TGFβ treatment repressing SOX9 expression in tumor cells lacking PTEN. Together, our study defined a critical role for PTEN-AKT2 signaling in maintaining liver epithelial lineage fidelity and revealed how its disruption promotes the conversion of mature hepatocytes or cholangiocytes into liver cancer stem-like cells (LCSCs). Furthermore, we identify a PTEN-dependent crosstalk between NOTCH and TGFβ pathways that governs liver tumor development. Together, this work provides mechanistic insight into lineage plasticity in liver cancer with implications for pathway-directed therapy.
    DOI:  https://doi.org/10.1038/s41388-026-03960-0
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