bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2026–06–07
sixteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Brieflow: an integrated computational pipeline for high-throughput analysis of optical pooled screening data.
  2. Interpretable decoding of cell fate from a snapshot of combinatorial signaling.
  3. High-content screening identifies mTORC1-independent TFEB activators that promote protective autophagy.
  4. Decoding PI3K isoform selectivity through an ensemble-based framework integrating correlated motions, allosteric networks, and hydration thermodynamics.
  5. 'Virtual cells' aim to turn raw data into predictive models of biology.
  6. Suppression of AKT Activation Through LZK Inhibition Limits Tumor Growth in Esophageal and Head and Neck Cancers.
  7. Hypoplastic lower extremity in a child with a mosaic PIK3CA variant.
  8. JCAD couples tight junction condensates to actin and RhoA to maintain the endothelial barrier.
  9. Neural crest cell signatures drive tumorigenesis in tuberous sclerosis complex and lymphangioleiomyomatosis.
  10. PerturbPlan: An analytical framework for designing Perturb-seq experiments.
  11. Embryo-scale Visual Cell Sorting reveals a conserved transcriptomic signature of nucleolar size linked to proteostasis.
  12. Nuclear SUN2 coordinates endothelial cell-matrix interactions to regulate blood vessel homeostasis and barrier function.
  13. Multiscale learning of gene network-driven phenotypic dynamics of single cells.
  14. Oncogenic cell fate decision in breast epithelial cells I: growth factors and mechanisms.
  15. Mechanobiology of solid tumor vasculature: implications for tumor progression.
  16. A pipeline for cell migration analysis in live-cell imaging data from human iPSC-derived forebrain assembloids.
  1. Nat Commun. 2026 May 30.
    Brieflow: an integrated computational pipeline for high-throughput analysis of optical pooled screening data.
    Matteo Di Bernardo, Roshan S Kern, Ana Karla Cepeda Diaz, Alexa Mallar, Samuel J Choi, Andrew Nutter-Upham, Sebastian Lourido, 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 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 5072 fitness-conferring genes, processing more than 70 million cells with multiple phenotypic markers. To accelerate biological interpretation, we additionally present MozzareLLM, a framework leveraging large language models to identify biological processes within phenotypic clusters and prioritize gene candidates for experimental validation. Our combined analysis recovers coherent biological modules missed by existing analytical approaches, including five core mitochondrial sub-programs absent from the original study. The modular design and open-source implementation of Brieflow facilitates the integration of new analytical components while ensuring computational reproducibility and improved performance for the use of high-content phenotypic screening in biological discovery.
    DOI:  https://doi.org/10.1038/s41467-026-73643-7
  2. bioRxiv. 2026 May 18. pii: 2026.05.17.725652. [Epub ahead of print]
    Interpretable decoding of cell fate from a snapshot of combinatorial signaling.
    Abdul-Bassit Fijabi, Seth Teague, Emily Freeburne, Hina Aftab Khan, Craig Johnson, David B Brückner, Idse Heemskerk.
      How combinatorial cell signaling controls cellular decisions in the face of crosstalk is a fundamental problem in biology. A key open question is whether a single snapshot of signaling is sufficient to predict cell fate, especially given substantial evidence that signaling dynamics shape fate decisions. Here, we show that a snapshot of combinatorial signaling accurately predicts cell fate at the single-cell level in a model for human embryonic patterning. To this end, we developed Sig2Fate, a quantitative method integrating iterative immunofluorescence, information theory, and machine learning. Cell fate is encoded by combinatorial yet redundant signaling that reduces to a single angular coordinate in the high-dimensional signaling space, providing a simple interpretation of the signal-to-fate map. This map generalizes across variations in BMP concentration and pharmacological perturbations of ERK, Wnt, and YAP signaling, enabling prediction of drug responses from control data alone when signaling crosstalk is accounted for. Our findings provide a framework for predicting and explaining complex phenotypes from signaling perturbations across biological systems.
    DOI:  https://doi.org/10.64898/2026.05.17.725652
  3. Biochem Biophys Res Commun. 2026 Jun 01. pii: S0006-291X(26)00841-7. [Epub ahead of print]827 154077
    High-content screening identifies mTORC1-independent TFEB activators that promote protective autophagy.
    Takashi Miyano, Kanzo Suzuki, Toshihiro Sera.
      Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway. It becomes active upon nuclear translocation and induces the expression of genes involved in autophagy and lysosomal function. Mechanistic target of rapamycin complex 1 (mTORC1) inhibition typically triggers this process; however, chronic mTORC1 suppression often induces adverse metabolic and proliferative effects, necessitating the identification of mTORC1-independent mechanisms driving TFEB nuclear translocation. Therefore, this study aimed to identify pharmacological activators of TFEB nuclear translocation that function independently of mTORC1 inhibition. In this study, we developed a high-content screening assay to quantify TFEB nuclear translocation in HeLa cells and screened a library of 560 approved compounds. We identified two compounds, NSC-319726 and ML-SA1, that promoted TFEB nuclear translocation without reducing p70S6K phosphorylation, supporting an mTORC1-independent mechanism. Both compounds significantly increased LC3-II accumulation and the signal intensity of an autolysosomal marker, indicating enhanced autophagic flux. Functionally, these compounds protected the cells against staurosporine-induced apoptosis and hydrogen peroxide-induced oxidative stress. Notably, pre-treatment conferred significantly greater protection than co-treatment, suggesting that TFEB-mediated transcriptional remodeling is necessary for maximal cytoprotection. Overall, these findings highlight the potential of high-content phenotypic screening to identify mTORC1-independent TFEB activators and suggest NSC-319726 and ML-SA1 as pharmacological inducers of protective autophagy in vitro.
    Keywords:  Autophagy; Cellular stress; Screening; TFEB; mTORC1
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154077
  4. J Biomol Struct Dyn. 2026 Jun 02. 1-35
    Decoding PI3K isoform selectivity through an ensemble-based framework integrating correlated motions, allosteric networks, and hydration thermodynamics.
    Kevser Kübra Kırboğa, Erhan Keles.
      Phosphoinositide 3-kinase (PI3K) isoform selectivity remains a central challenge in cancer therapeutics, as highly conserved ATP-binding domains hinder the development of specific inhibitors while broad inhibition leads to severe toxicities. Here, we introduce a computational framework that integrates molecular dynamics (MD), residue-network analysis, and hydration thermodynamics to define the molecular determinants of PI3K isoform selectivity. Across 100-ns all-atom simulations of class I PI3K isoforms (α, β, γ, δ), we identify distinct 'dynamic signatures' rather than static pocket differences. PI3Kα and PI3Kβ exhibit the greatest structural stability, whereas PI3Kδ shows the largest conformational deviation, and PI3Kγ displays exceptional plasticity, reflecting a unique mechanism of dynamic regulation. Network analysis highlights isoform-specific supercritical hubs (SER838 in α, SER841 in β, SER815 in δ, and ASP849 in γ) that are predicted to act as bottlenecks of allosteric communication. Importantly, druggability emerges independently of pocket size; although PI3Kβ has the largest cavity, PI3Kγ is predicted to be the most druggable, consistent with favorable water displacement around hydrophobic rims and thermodynamically challenging hydration near polar hubs. Hydrogen bond residence time analysis independently validated the hydration site classifications, revealing a strong correlation (R2 = 0.91) between water residence times and hydration site free energies across all 20 supercritical residues. Together, these findings suggest that isoform selectivity may be primarily governed by dynamic ensembles, allosteric pathways, and water-mediated interactions, establishing a computational hypothesis framework to guide the future rational design of isoform-selective PI3K inhibitors that target dynamic rather than purely static features.
    Keywords:  PI3K isoform selectivity; allosteric communication; conformational dynamics; molecular dynamics simulations; selective inhibitors
    DOI:  https://doi.org/10.1080/07391102.2026.2680471
  5. Nature. 2026 Jun;654(8117): 286-288
    'Virtual cells' aim to turn raw data into predictive models of biology.
    Michael Eisenstein.
      
    Keywords:  Machine learning; Systems biology; Technology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-026-01731-1
  6. Mol Cancer Ther. 2026 Jun 02.
    Suppression of AKT Activation Through LZK Inhibition Limits Tumor Growth in Esophageal and Head and Neck Cancers.
    Meghri Katerji, Maxine R Rubin, Eric Lindberg, Pedro Torres-Ayuso, Aamna Siddiqui, Amy L Funk, Katherine Nyswaner, Carolyn C Woodroofe, Sarah Wolfe, Zoe C Edwards, Eleanor W Trotter, Erkan Baloglu, Ivan Ahel, Anna A Marusiak, Alexandra Newton, Raul E Cachau, Kiranya Arnold, Rolf E Swenson, John Brognard.
      Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers worldwide due to its aggressive nature and lack of knowledge of underlying oncogenic drivers, limiting treatment options. Approximately 60% of ESCC cases have amplification/overexpression of MAP3K13, which encodes the kinase LZK. Here, we found that MAP3K13-amplified ESCC exhibit therapeutic dependency on LZK, and that small-molecule inhibition of its catalytic function decreased the viability of ESCC cells with amplified MAP3K13. Inhibition of LZK suppressed tumor growth in MAP3K13-amplified ESCC patient-derived xenograft mice treated orally with a newly described LZK inhibitor. We discovered that LZK is required to sustain AKT activation in ESCC and HNSCC, where depletion, degradation, or treatment with the LZK inhibitor GNE-3511 or an improved inhibitor suppressed AKT activation. AKT activation could be rescued by expression of an LZK drug-resistant mutant, indicating suppression was specific to LZK. AKT and LZK co-localized and interacted in cells, and LZK enhanced AKT phosphorylation at S473 and T450 in vitro. This pattern of AKT phosphorylation reflected a non-catalytic scaffold function of LZK, as LZK inhibitors did not suppress AKT activation and a kinase-dead LZK mutant promoted AKT activation. AKT inhibitors reduced LZK-induced activation of AKT, indicating LZK facilitates AKT autophosphorylation. Furthermore, GNE-3511 inhibited the interaction of LZK with AKT in co-immunoprecipitation experiments. Molecular modeling supported a mechanism whereby LZK binds and dislodges AKT's PH domain to promote AKT autophosphorylation. Our findings demonstrate that MAP3K13-amplified tumors are dependent on LZK-mediated AKT scaffolding, supporting LZK inhibition as a therapeutic strategy in ESCC and HNSCC.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-1042
  7. JAAD Case Rep. 2026 Jun;72 174-176
    Hypoplastic lower extremity in a child with a mosaic PIK3CA variant.
    Sabine Obagi, Joseph Dodson, Timothy James Maarup, Jingyun Gao.
      
    Keywords:  PIK3CA; PIK3CA-related altered growth spectrum; growth disorders; mosaicism; pediatrics; vascular malformations
    DOI:  https://doi.org/10.1016/j.jdcr.2026.03.043
  8. bioRxiv. 2026 May 21. pii: 2026.05.19.725802. [Epub ahead of print]
    JCAD couples tight junction condensates to actin and RhoA to maintain the endothelial barrier.
    Kyle A Jacobs, Yoon-Gu Jang, Fang-Shiuan Leung, Lakyn N Mayo, Torsten Wittmann, Jeffrey O Bush, Matthew L Kutys.
      How endothelial cell-cell junctions integrate cytoskeletal, adhesive, and local signaling networks to maintain vascular barrier integrity remains incompletely defined. Here, we identify junctional cadherin 5-associated protein (JCAD) as a modular scaffold that organizes endothelial tight junction architecture by coupling junctional condensates to actin and RhoA signaling. Genetic deletion of Jcad in mice does not affect baseline vascular permeability but causes inflammation-dependent barrier hyperpermeability. JCAD depletion in primary human endothelial cells disrupts tight junction continuity and increases paracellular permeability. Mechanistically, JCAD localizes to ZO-1-positive tight junctions independently of VE-cadherin, directly binds filamentous actin, and forms dynamic actin-associated condensates at cell-cell contacts. Structure-function analysis reveals separable domains mediating tight junction targeting and actin binding, establishing a bipartite architecture that distinctly coordinates junctional signaling and cytoskeletal coupling. Together, these findings identify JCAD as a cell-cell adhesion scaffold that integrates the phase-separated tight junction plaque with actin and RhoA-dependent mechanics, enabling endothelial barrier adaptation to inflammatory stress.
    DOI:  https://doi.org/10.64898/2026.05.19.725802
  9. JCI Insight. 2026 Jun 02. pii: e195013. [Epub ahead of print]
    Neural crest cell signatures drive tumorigenesis in tuberous sclerosis complex and lymphangioleiomyomatosis.
    Uchenna J Unachukwu, Enio B Garcia, Nooralam Rai, Jeanine M D'Armiento.
      Tuberous sclerosis complex (TSC) and Lymphangioleiomyomatosis (LAM) lack well-defined cellular origins, limiting treatment options. In this report, scRNA-seq of Tsc2+/- mouse renal cystadenomas revealed an 80-fold increase in a tumor cell subpopulation with neural crest features, and expressing known cranial neural crest genes as SRY box transcription factor 9 (Sox9), transcription factor activator protein (Tfap2a), and candidate neurocristopathy markers, osteopontin (Spp1), lipocalin-2 (Lcn2), clusterin (Clu), and cytokeratin 18 (Krt18). These signatures were validated in mouse tumors, and LAM patient lesions and serum, identifying a tumor phenotype distinct from traditional VEGFD detection. Pathway analysis indicated activation of WNT/SHH signaling, nephric duct formation, and pro-tumorigenic signals, with transcription factor 7 (Tcf7) and ephrin-A ligands as key upstream regulators. Spp1 KO in cranial neural crest cells (CNCCs) significantly reduced proliferation (28-33%), migration (54-76%), and invasion (29-64%) without affecting viability, while Tsc2 KO increased viability 3 to 6-fold with minimal impact on chemotaxis. Elevated serum levels of SPP1 and KRT18 in some LAM patients, decreased LCN2 in nearly all, and distinct increases in VEGFD suggest complementary roles for these biomarkers. Overall, findings support a neurocristopathic model of tumor development in TSC and LAM and identify potential biomarkers and therapeutic targets beyond mTOR inhibition.
    Keywords:  Biomarkers; Cancer; Cell biology; Clinical Research; Oncology; Stem Cells
    DOI:  https://doi.org/10.1172/jci.insight.195013
  10. bioRxiv. 2026 May 23. pii: 2026.05.22.727199. [Epub ahead of print]
    PerturbPlan: An analytical framework for designing Perturb-seq experiments.
    Ziang Niu, Yihui He, James Galante, Andreas R Gschwind, Judhajeet Ray, Lars M Steinmetz, Jesse M Engreitz, Eugene Katsevich.
      CRISPR screens with single-cell RNA-seq readouts provide a powerful tool for characterizing the functions of noncoding elements and genes. However, designing these experiments to balance statistical power and cost is challenging, given the large number of design parameters. The only available tool for this purpose is a simulation-based power calculator, but it is computationally costly and requires high-performance computing to run. We derive a novel analytical formula for the power to detect perturbation-expression associations, recapitulating power estimates from the simulation-based tool while reducing runtime by up to seven orders of magnitude. This acceleration unlocks the possibility of interactive single-cell CRISPR screen design. Accordingly, we develop PerturbPlan, an interactive web application built on the analytical power formula. PerturbPlan helps users address 11 design questions for two types of single-cell CRISPR screens, Perturb-seq and targeted Perturb-seq (TAP-seq). We apply PerturbPlan to carry out a comparative analysis of three recent Perturb-seq designs, demonstrating how optimal design varies across experiments of different scales. We also use PerturbPlan to quantify the cost savings of a recent TAP-seq study relative to a hypothetical Perturb-seq study assaying the same perturbations, illustrating how the tool can inform decisions about targeted versus whole-transcriptome readouts. In sum, PerturbPlan is the first tool to facilitate flexible and interactive design of well-powered single-cell CRISPR screen experiments.
    DOI:  https://doi.org/10.64898/2026.05.22.727199
  11. bioRxiv. 2026 May 26. pii: 2026.05.25.727721. [Epub ahead of print]
    Embryo-scale Visual Cell Sorting reveals a conserved transcriptomic signature of nucleolar size linked to proteostasis.
    Hyeon-Jin Kim, Sriram Pendyala, Josephine Lin, Tony Cooke, Gang Li, William Stafford Noble, Xinxian Deng, Christine M Disteche, Cole Trapnell, Douglas M Fowler.
      Nucleoli, nuclear speckles and other compartments regulate transcription, RNA processing, and chromatin organization within the nucleus, yet the relationship of their morphology to developmental gene expression programs in vivo is poorly understood. Here, we develop a high-throughput Visual Cell Sorting (VCS) workflow for fixed cells and nuclei that combines antibody-based photoconversion; GPU-accelerated, real-time image analysis; and three-level single-cell combinatorial indexing RNA-seq (sci-RNA-seq3) to link nuclear compartment morphology to single-nucleus transcriptomes at embryo scale. We use VCS to analyze and sort over 1 million mouse embryo-derived nuclei by nucleolar, nuclear speckle, or nuclear size and construct a transcriptional atlas annotated with nuclear compartment phenotypes. Nuclear compartment size varies both between and within lineages and is shaped by proliferation and differentiation. In extracellular matrix protein-producing cell types such as fibroblasts, chondrocytes, and osteoblasts, nucleolar enlargement is uncoupled from cell cycle, and in erythroid cells exhibit a sharp nucleolar contraction preceding cell-cycle exit. We identify a 41-gene transcriptional signature whose expression tracks nucleolar size, enriched for ribosome biogenesis, mitochondrial metabolism, unfolded protein response, stress granule, and ubiquitin-proteasome pathway components. We used this nucleolar transcriptional signature to annotate mouse, zebrafish and human developmental atlases with nucleolar size information, revealing a conserved coupling between nucleolar activity and proteostasis programs. Our work establishes Visual Cell Sorting as a scalable platform for mapping image-based phenotypes to molecular programs; details the relationship between nuclear compartment phenotypes and development; and provides a transcriptional signature to estimate nucleolar size from existing single-cell datasets.
    DOI:  https://doi.org/10.64898/2026.05.25.727721
  12. bioRxiv. 2026 May 20. pii: 2026.05.18.725979. [Epub ahead of print]
    Nuclear SUN2 coordinates endothelial cell-matrix interactions to regulate blood vessel homeostasis and barrier function.
    Pauline Bougaran, Danielle B Buglak, Alexandra Neal, Mitesh Rathod, Michaelanthony Gore, Max A Hockenberry, Aryan A Amin, Natalie Tanke, Morgan Oatley, Wesley R Legant, Ziqing Liu, James E Bear, William J Polacheck, Victoria L Bautch.
      Vascular endothelial cells respond to environmental forces to remodel vessels during development and to achieve homeostasis, and mis-regulated responses lead to vascular dysfunction and disease. The nucleus participates in force transduction to cell-matrix junctions via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex that resides in the nuclear envelope, but how these forces are regulated and relayed is incompletely understood. We found that the LINC complex protein SUN2 is required for proper endothelial cell-matrix interactions that occur far from the nucleus and affect angiogenic expansion, vascular responses to flow, and barrier integrity. Endothelial cells lacking SUN2 had inappropriate flow responses and reduced expression of flow-mediated transcription factors in vitro and in vivo . Expression of several matrix and adhesion genes was reduced in SUN2-depleted cells, leading to defective extracellular matrix, dysmorphic focal adhesions resistant to dynamic turnover, and disturbed cell-matrix force distribution. Mechanistically, nuclear SUN2 affected dynamic regulation of the microtubule cytoskeleton that correlated with matrix metalloprotease-dependent barrier dysfunction. These findings indicate that nuclear SUN2 establishes and maintains blood vessel homeostasis by controlling microtubule-mediated effects on focal adhesion turnover and extracellular matrix properties, with implications for cardiovascular aging and diseases such as Marfan syndrome that affect vessel wall integrity.
    DOI:  https://doi.org/10.64898/2026.05.18.725979
  13. Mol Syst Biol. 2026 Jun 05.
    Multiscale learning of gene network-driven phenotypic dynamics of single cells.
    Dongyan Zhang, Jinan Li, Qing Nie, Xiaoqiang Sun.
      Understanding how gene regulatory networks (GRNs) dynamically orchestrate cell fate emergence remains a fundamental challenge. Here, we present GRNvelo, a computational framework that reconstructs multiscale cell fate dynamics by integrating GRNs with phenotypic dynamics from temporal single-cell RNA-seq data. GRNvelo establishes a biologically interpretable and mathematically rigorous multiscale model that couples GRN-driven single-cell velocity with nonlocal cell growth-mediated population dynamics. To operationalize this model, GRNvelo devises a two-phase cooperative optimization algorithm based on physics-informed neural networks (PINNs): TC-PINN for jointly inferring GRN velocity and latent time, and MP-PINN for refining GRN velocity within the context of cell population dynamics. In benchmark evaluations, GRNvelo demonstrates superior performance across two synthetic datasets and four real datasets, including branching development and diverse perturbation-response scenarios. Collectively, GRNvelo not only accurately infers GRN-driven cell fate dynamics but also predicts altered cell fates in response to diverse genetic perturbations, including dynamic and combined ones, thus establishing a new computational paradigm for predicting and modulating cell fate outcomes.
    DOI:  https://doi.org/10.1038/s44320-026-00220-x
  14. Res Sq. 2026 May 22. pii: rs.3.rs-9365348. [Epub ahead of print]
    Oncogenic cell fate decision in breast epithelial cells I: growth factors and mechanisms.
    Divya Murali, Shakti Gupta, Shankar Subramaniam.
       BACKGROUND: Breast cancer cell heterogeneity and cellular fate are governed by a variety of molecular mechanisms. The LINCS (Library of Integrated Network-based Cellular Signatures) consortium performed multi-omics experiments on normal breast epithelial cells, MCF10a, to deduce temporal mechanisms of regulation and cell state signatures contributing to pro-oncogenic phenotypes.
    METHODS: Normal breast epithelial cells were treated with oncogenic ligands such as EGF, HGF, and OSM, and multi-modal measurements including Reverse phase protein Assay (RPPA), RNA-seq, ATAC-seq, and Cyclic immune-fluorescence (Cyclic-IF) were performed.
    RESULT: In our integrated analyses of the data to elucidate mechanisms, contextual functional networks were constructed by integrating protein signaling, transcription factor activity, and gene expression. Phenotypic changes in response to the ligands consisted of cell cycle modifications leading to oncogenic events such as loss of apoptosis and induction of EMT (Epithelial to Mesenchymal Transition). Activation of mTOR was observed with all ligands, which led to the activation of E2F1. Downstream transcriptomic regulation of E2F1 led to an increase in both oncogenic signaling and EMT. Additionally, under OSM treatment, activation of STAT3 facilitated the enhancement of EMT via transcriptomic regulation of JUN and FOS. These findings were further validated using the chromatin changes seen in ATAC-seq and protein localization as seen in Cyclic-IF assay.
    CONCLUSION: This analysis provides valuable insights into the mechanisms of transcriptional regulation during oncogenesis in normal breast cells treated with growth factors and can aid in the discovery of novel drug targets and treatments.
    DOI:  https://doi.org/10.21203/rs.3.rs-9365348/v1
  15. Cancer Metastasis Rev. 2026 Jun 02. pii: 37. [Epub ahead of print]45(2):
    Mechanobiology of solid tumor vasculature: implications for tumor progression.
    Raghu Vamsi Kondapaneni, Sarah Libring, Sid Dsa, Cynthia A Reinhart-King.
      Under normal physiological conditions, the vasculature forms a selective barrier that regulates molecular and cellular transport, largely maintained through vascular endothelial cadherin (VE-cadherin)-mediated junctions formed by endothelial cells. However, in the tumor microenvironment (TME) of solid tumors, the vasculature is disrupted due to biochemical and mechanical signals. In this review, we discuss the latest studies that describe how various mechanical forces in the TME, including matrix stiffening, fluid shear stress, compressive forces, and interstitial fluid pressures, influence the mechanical phenotype of endothelial cells, including vascular integrity and angiogenesis. Additionally, we emphasize how these forces activate key mechanotransduction pathways, notably actin cytoskeletal reorganization through RhoA activation, downstream of FAK/Src and YAP/TAZ signaling, and remodel the tumor vasculature by increasing vascular permeability and neovascularization. Overall, we summarize the pivotal role of mechanotransduction in vascular barrier disruption and angiogenesis, providing new avenues for therapeutic strategies targeting tumor vasculature.
    Keywords:  Angiogenesis; Matrix stiffness; Mechanotransduction; Metabolism; Shear stress; Vascular integrity; Vascular permeability
    DOI:  https://doi.org/10.1007/s10555-026-10345-y
  16. bioRxiv. 2026 May 18. pii: 2026.05.17.725711. [Epub ahead of print]
    A pipeline for cell migration analysis in live-cell imaging data from human iPSC-derived forebrain assembloids.
    Maya P Weidman, Natalie Baker Campbell, Cody Headings, Samantha Chung, Musarat Khan, Aarnav Kandukuri, Vianne Lim, Gloria Olubowale, Michelle Kim, Anna Devor, Ella Zeldich, Martin Thunemann.
      During forebrain development, inhibitory interneurons and oligodendrocyte progenitor cells migrate long distances into the developing dorsal cortex. Human induced pluripotent stem cell-derived forebrain assembloids (FAs) provide direct experimental access to this migratory process in vitro. Using viral labeling to express yellow fluorescent protein (EYFP) and tandem-dimer tomato (tdTomato) driven by EF1α or SOX10 promoters, respectively, we tracked cells in FAs over 15-17h using spinning disk confocal microscopy. We developed an end-to-end processing pipeline for 4D volumetric imaging data, consisting of background subtraction and drift correction, manual cell coordinate tracking, and an analysis workflow to describe migratory cell behavior. Image preprocessing significantly improved data quality for subsequent manual tracking in datasets with heterogeneous labeling density and brightness. Trajectory analysis of 336 EYFP- and 337 tdTomato-labeled cells from twelve FAs indicates that most cells show super-diffusive directed motility. Our pipeline represents a key resource for cell tracking in FAs and similar three-dimensional platforms. This pipeline represents the first open tracking resource for iPSC-derived FAs and can be used as a ground-truth resource for the development of automated cell detection and tracking algorithms.
    DOI:  https://doi.org/10.64898/2026.05.17.725711
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