bims-pideca 2025-11-02 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2025–11–02
ten papers selected by
Ralitsa Radostinova Madsen, MRC-PPU

Targeted management of vascular anomalies.
Non-equilibrium strategies enabling ligand specificity by signaling receptors.
PI3Kα inhibitor and degrader inavolisib can co-opt FGFR2 to enhance responses in patients with PIK3CA-mutated solid tumors and in preclinical models.
Anomaly detection for high-content image-based phenotypic cell profiling.
The receptor tyrosine kinase ErbB2/HER2 governs CDK4 inhibitor sensitivity, timing and irreversibility of the G1/S transition.
Spatial artifact detection improves the reproducibility of drug screening experiments.
Designing insulin receptor agonists.
Akt/PKB Functions in Cell Migration and Invasion.
connectomeDB2025: a rigorously curated, multi-species resource of experimentally supported ligand-receptor interactions.
Tissue microenvironment dictates the state of human iPSC-derived endothelial cells of distinct developmental origin in 3D cardiac microtissues.

J Eur Acad Dermatol Venereol. 2025 Oct 28.

Targeted management of vascular anomalies.

Jessie T Lu, Marra Aghajani, Deshan F Sebaratnam.

  Advances in genetic sequencing technology have enabled identification of the somatic and germline variants that underlie many vascular anomalies. These pathogenic variants often affect one of two signalling pathways: (1) the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway and (2) the RAS (rat sarcoma)/RAF (rapidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) pathway. This narrative review aims to synthesize the existing knowledge on the genetic origin of vascular anomalies and the targeted therapeutic approaches. A literature search was conducted using PubMed, Google Scholar and EMBASE, with a key focus on genetic pathways and emerging therapies. mTOR inhibitors have shown efficacy in a range of venous, lymphatic, capillary and syndromic vascular malformations. PIK3CA inhibitors are already commonly used in the treatment of PIK3CA-related overgrowth spectrum (PROS), with current research into new mutant-specific inhibitors aiming to improve selectivity and reduce toxicity. AKT inhibitors are being trialled in Proteus syndrome and PROS. MEK inhibitors have shown efficacy in the treatment of capillary malformations with arteriovenous malformations (CM-AVM) and both MEK and BRAF inhibitors are being investigated for use in extracranial AVMs. Vascular anomalies were previously orphan diseases with minimal effective therapeutic approaches. The discovery of the precise molecular pathways underlying these anomalies has allowed existing drugs to be repurposed for genotype-guided management, enabling a 'personalized' approach to patient care.

Keywords:  birthmarks; cutaneous manifestations of systemic disease; general dermatology; genodermatoses; vascular anomalies

DOI:  https://doi.org/10.1111/jdv.70151
Elife. 2025 Oct 29. pii: RP107524. [Epub ahead of print]14

Non-equilibrium strategies enabling ligand specificity by signaling receptors.

Andrew Goetz, Jeremy Barrios, Ralitsa Radostinova Madsen, Purushottam D Dixit.

  Signaling receptors often encounter multiple ligands and have been shown to respond selectively to generate appropriate, context-specific outcomes. At thermal equilibrium, ligand specificity is limited by the relative affinities of ligands for their receptors. Here, we present a non-equilibrium model in which receptors overcome thermodynamic constraints to preferentially signal from specific ligands while suppressing others. In our model, multi-site phosphorylation and active receptor degradation act in concert to regulate ligand specificity, with receptor degradation, a common motif in eukaryotes, providing a previously under-appreciated layer of control. Here, ligand-bound receptors undergo sequential phosphorylation, with progression restarted by ligand unbinding or receptor turnover. High-affinity complexes are kinetically sorted toward degradation-prone states, while low-affinity complexes are sorted toward inactivated states, both limiting signaling. As a result, network activity is maximized for ligands with intermediate affinities. This mechanism explains paradoxical experimental observations in receptor tyrosine kinase signaling, including non-monotonic dependence of signaling output on ligand affinity and kinase activity. Given the ubiquity of multi-site phosphorylation and ligand-induced degradation across signaling receptors, we propose that kinetic sorting may be a general non-equilibrium ligand-discrimination strategy used by multiple signaling receptors.

Keywords:  computational biology; human; physics of living systems; proofreading; signaling networks; specificity; systems biology

DOI:  https://doi.org/10.7554/eLife.107524
Clin Cancer Res. 2025 Oct 27.

PI3Kα inhibitor and degrader inavolisib can co-opt FGFR2 to enhance responses in patients with PIK3CA-mutated solid tumors and in preclinical models.

Dejan Juric, Kyung Song, Radia M Johnson, Melissa K Accordino, Philippe L Bedard, Andrés Cervantes, Valentina Gambardella, Erika Hamilton, Antoine Italiano, Kevin Kalinsky, Ian E Krop, Mafalda Oliveira, Cristina Saura, Peter Schmid, Nicholas C Turner, Andreea Varga, Steven Gendreau, Michael S Hwang, Zheng Kuang, Jeffrey T Lau, Eva Lin, Trang Pham, Danilo Maddalo, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Scott Martin, Nicole M Sodir, Ethan S Sokol, Zachary J Whitfield, Alice Wong, Robert L Yauch, Junko Aimi, Sravanthi Cheeti, Jill Fredrickson, Stephanie Hilz, Marc Hafner, Katherine E Hutchinson, Yanling Jin, Ubong Peters, Daniel Zingg, Stephanie Royer-Joo, Noopur Shankar, Jennifer L Schutzman, Komal L Jhaveri, Anwesha Dey.

BACKGROUND: PIK3CA mutations frequently drive solid tumors, particularly hormone receptor-positive (HR+) breast cancer. Inavolisib, an ATP-competitive p110α inhibitor, also promotes the degradation of mutated p110α. PI3K inhibitors have generally shown modest single-agent activity and have safety concerns.
METHOD: A first-in-human Phase 1 study (NCT03006172) evaluated oral inavolisib in patients with PIK3CA-mutated solid tumors, to determine the maximum tolerated dose (MTD) and safety. Correlative analyses included circulating tumor DNA (ctDNA). Preclinical studies in cell lines and xenografts elucidated the role of FGFR2.
RESULTS: The MTD was 9 mg daily, with a manageable safety profile (e.g., hyperglycemia, diarrhea). Inavolisib showed linear pharmacokinetics, consistent pharmacodynamic modulation, and antitumor activity in HR+ PIK3CA-mutated breast cancer (26% objective response rate, 45% clinical benefit rate). FGFR2 hotspot mutations in ctDNA were strongly associated with clinical benefit. Preclinically, oncogenic FGFR2 signaling enhanced inavolisib sensitivity by engaging HER3, RAS, and p85β, that facilitated mutated p110α degradation, surpassing non-degrading inhibitors. Combination therapy with FGFR2 inhibitors showed synergy and delayed resistance.
CONCLUSION: These findings highlight a novel cooperativity between FGFR2 and p110α that boosts the effectiveness of inavolisib. The data support advancing precision oncology beyond single biomarkers to complex algorithms utilizing co-occurring alterations, particularly suggesting that combining inavolisib with FGFR2 inhibitors may offer enhanced and more durable responses in PIK3CA/FGFR2-altered tumors.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-1459
Cell Syst. 2025 Oct 29. pii: S2405-4712(25)00262-5. [Epub ahead of print] 101429

Anomaly detection for high-content image-based phenotypic cell profiling.

Alon Shpigler, Naor Kolet, Shahar Golan, Erin Weisbart, Assaf Zaritsky.

  High-content image-based phenotypic profiling combines automated microscopy and analysis to identify phenotypic alterations in cell morphology and provide insight into the cell's physiological state. Classical representations of the phenotypic profile cannot capture the full underlying complexity in cell organization, while recent weakly supervised machine-learning-based representation-learning methods are hard to biologically interpret. We used the abundance of control wells to learn the in-distribution of control experiments and used it to formulate a self-supervised reconstruction anomaly-based representation that encodes the intricate morphological inter-feature dependencies while preserving the representation interpretability. The performance of our anomaly-based representations was evaluated for downstream tasks with respect to two classical representations across four public Cell Painting datasets. Anomaly-based representations improved reproducibility and mechanism of action classification and complemented classical representations. Unsupervised explainability of autoencoder-based anomalies identified specific inter-feature dependencies causing anomalies. The general concept of anomaly-based representations can be adapted to other applications in cell biology. A record of this paper's transparent peer review process is included in the supplemental information.

Keywords:  anomaly detection; explainability; high-content image-based cell profiling

DOI:  https://doi.org/10.1016/j.cels.2025.101429
J Biol Chem. 2025 Oct 27. pii: S0021-9258(25)02717-6. [Epub ahead of print] 110865

The receptor tyrosine kinase ErbB2/HER2 governs CDK4 inhibitor sensitivity, timing and irreversibility of the G1/S transition.

Ayaka Nagasato-Ichikawa, Ken Murakami, Kazuhiro Aoki, Mariko Okada.

  Cell cycle entry and the irreversible transition from the G1 to S phase are crucial for mammalian cell proliferation. Among the ErbB family, the ErbB2/HER2 receptor is a key driver of cancer growth. However, the quantitative mechanisms underlying the ErbB2-mediated G1/S transition remain unclarified. Here, we performed an extensive time-course analysis of high and low ErbB2-expressing breast cancer cells to describe the regulatory mechanisms of the ErbB2-mediated G1/S transition. Live-cell imaging using cell cycle reporters revealed that the G1/S transition occurs 20 h after ErbB2 activation, driven primarily by the cyclin D1/CDK4-RB axis. Hsp90 is regulated by CDK4 activity and controls the stability of ErbB2 protein in a time-dependent manner. CDK4 inhibitor treatment arrested the cell cycle in most cells; a subpopulation showed a 25-h delay in G1/S entry associated with enhanced c-Myc activation. In high ErbB2-expressing cells, CDK4 inhibition led to c-Myc overactivation, a rapid decrease in cyclin D1 expression, and cell cycle arrest. Overall, we demonstrate how ErbB2 receptor levels modulate the roles of cyclin D1 and c-Myc in the G1/S transition and suggest that variations in ErbB2 levels within breast cancer tissues confer heterogeneous sensitivity to CDK4 inhibitors, potentially complicating treatment.

Keywords:  Myc; breast cancer; cell cycle; cell signaling; cyclin D1

DOI:  https://doi.org/10.1016/j.jbc.2025.110865
iScience. 2025 Oct 17. 28(10): 113470

Spatial artifact detection improves the reproducibility of drug screening experiments.

Aleksandr Ianevski, Kristen Nader, Swapnil Potdar, Alexandra Gorbonos, Filipp Ianevski, Ziaurrehman Tanoli, Jani Saarela, Tero Aittokallio.

  Reliable and reproducible drug screening experiments are essential for drug discovery and personalized medicine. We demonstrate how systematic experimental errors in drug plates negatively impact data reproducibility, and that conventional quality control (QC) methods based on plate controls fail to detect these spatial errors. To address this limitation, we developed a control-independent QC approach that uses normalized residual fit error (NRFE) to identify systematic artifacts in drug screening experiments. Analysis of >100,000 duplicate measurements from the PRISM pharmacogenomic study revealed that NRFE-flagged experiments show 3-fold lower reproducibility among technical replicates. By integrating NRFE with QC methods to analyze 41,762 matched drug-cell line pairs between two datasets from the Genomics of Drug Sensitivity in Cancer project, we improved the cross-dataset correlation from 0.66 to 0.76. Available as an R package at https://github.com/IanevskiAleksandr/plateQC, plateQC provides a robust toolset for enhancing drug screening data reliability and consistency for basic research and translational applications.

Keywords:  Bioinformatics; Biological sciences; Natural sciences; Pharmacoinformatics

DOI:  https://doi.org/10.1016/j.isci.2025.113470
Nat Rev Drug Discov. 2025 Oct 29.

Designing insulin receptor agonists.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-025-00175-y
Curr Top Microbiol Immunol. 2025 Oct 30.

Akt/PKB Functions in Cell Migration and Invasion.

Jennifer L Gorman, James R Woodgett.

Cell migration is an enormously complex process that requires sophisticated regulation and exquisite coordination of many cellular proteins that must act in a temporally and spatially orchestrated manner to achieve directional motion. Much like neuromuscular control of gait and walking, except within a single cell, a series of rapid feedback mechanisms must act in a cyclical manner to result in movement. The protein-serine kinase Akt/PKB that acts downstream of phosphatidylinositol 3' kinase (PI3K) activation is intricately involved in normal cell migration and in aberrant movement (e.g., cancer metastasis), but its role can be either pro- or anti-migration depending on cellular context. These contradictory effects likely reflect the nature of cellular motion, in that perturbations that disturb the continuity or integrity of migratory machines tend to be inhibitory. In contrast, increasing overall efficiency/coordination of the processes results in greater mobility. The net result of modulating Akt/PKB is therefore highly dependent upon other inputs into the cell and their context. Here, we briefly describe the molecular events associated with cellular migration, then describe current knowledge of Akt/PKB targets involved in this process, and conclude by discussing implications for suppression of cancer dissemination.

DOI: https://doi.org/10.1007/82_2025_333
Nucleic Acids Res. 2025 Oct 31. pii: gkaf1108. [Epub ahead of print]

connectomeDB2025: a rigorously curated, multi-species resource of experimentally supported ligand-receptor interactions.

Peiwen Liu, Sakura Eri B Maezono, Weitao Lin, Yen Yeow, Ya-Yu Liu, Yasmin Hisham, Rui Hou, Jordan A Ramilowski, Alistair R R Forrest.

Inferring cell-cell communication networks is now a cornerstone of single-cell RNA-seq and spatial transcriptomics data analysis, relying critically on reference catalogues of experimentally supported ligand-receptor interactions. Here, we present the updated, rigorously curated connectomeDB, an open-access database of peptide-based ligand-receptor pairs comprising 3579 vertebrate interactions supported by primary experimental evidence from 2803 research articles. By critically reviewing all putative ligand-receptor pairs from connectomeDB2020, CellChatDB v2, CellPhoneDB v5, CellTalkDB, ICELLNET v2, and LIANA+, we first removed over 2900 misclassified or unsupported interactions lacking primary-literature evidence. We then expanded the resulting verified dataset through AI-assisted literature mining and manual curation, adding 827 pairs and 718 supporting articles absent from other databases, including 264 pairs first described since 2020. connectomeDB2025 contains 5429 evidence links ("triplets"), each connecting a ligand-receptor pair to a specific publication, collectively providing at least one source of primary experimental evidence for each interaction. Notably, 2359 of these triplets are exclusive to connectomeDB2025, making it the most robustly supported ligand-receptor database with primary experimental evidence. The online resource (https://connectomedb.org) provides searchable, downloadable ligand-receptor lists and detailed pair summaries, enabling accurate cell-cell communication analysis across human, mouse, and 12 other vertebrate species.

DOI: https://doi.org/10.1093/nar/gkaf1108
iScience. 2025 Oct 17. 28(10): 113611

Tissue microenvironment dictates the state of human iPSC-derived endothelial cells of distinct developmental origin in 3D cardiac microtissues.

Xu Cao, Maria Mircea, Sara Cascione, Atoosa Amel, Theano Tsikari, Francijna E van den Hil, Hailiang Mei, Katrin Neumann, Anna Alemany, Konstantinos Anastassiadis, Christine L Mummery, Stefan Semrau, Valeria V Orlova.

  Each tissue and organ in the body has its own type of vasculature. Here, we demonstrate that organotypic vasculature for the heart can be recreated in a three-dimensional cardiac microtissue (MT) model composed of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), cardiac fibroblasts (CFs), and endothelial cells (ECs). ECs in cardiac MTs upregulated expression of markers enriched in human intramyocardial ECs, including CD36, CLDN5, APLNR, NOTCH4, IGFBP3, and ARHGAP18. We further show that the local microenvironment largely dictates the organ-specific identity of hiPSC-derived ECs: we compared ECs derived from cardiac and paraxial mesoderm and found that, regardless of origin, they acquired similar identities upon integration into cardiac MTs. Overall, the results indicated that while the initial gene profile of ECs was dictated by developmental origin, this could be modified by the local tissue environment. This developmental "plasticity" in ECs has implications for multiple pathological and disease states.

Keywords:  Developmental biology; Stem cells research; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2025.113611