bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2026–10–11
sixteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Mapping transcriptional responses to cellular perturbations with RNA fingerprinting.
  2. Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism.
  3. PI3Kδ is selectively inhibited by roginolisib by stabilizing the C-terminal helix kα12.
  4. Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer.
  5. Mechanism of activation of an ancestral TEC kinase by PIP3.
  6. PI3K is the dominant signalling pathway recruited by IRS proteins to mediate their effects on metabolism and growth.
  7. Insulin mimetics and non-canonical insulin receptor signaling: mechanisms and disease relevance.
  8. Klotho Deficiency Impairs Distal Potassium Homeostasis Through mTORC1-Dependent Suppression of ROMK.
  9. Coactivators YAP and TAZ Contribute Differently to the Transcriptional Regulation of VWF in Endothelial Cells.
  10. Comprehensive lineage tracing maps the landscape of cell fate decisions in mouse embryogenesis.
  11. A DNA Typewriter records the cell lineage history of a mouse, from zygote to late organogenesis.
  12. Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling.
  13. ESR1 mutations are associated with enhanced MTORC1 signaling in a context-dependent manner.
  14. Mastodon: the command center for large-scale lineage-tracing microscopy datasets.
  15. A fluctuation test for gastruloid heterogeneity.
  16. The conformation-selective PI3Kδ inhibitor roginolisib in patients with advanced or metastatic cancer, including metastatic uveal melanoma: first-in-human clinical trial.
  1. Cell. 2026 Oct 09. pii: S0092-8674(26)01119-0. [Epub ahead of print]
    Mapping transcriptional responses to cellular perturbations with RNA fingerprinting.
    Isabella N Grabski, Junsuk Lee, John D Blair, Carol Dalgarno, Isabella Mascio, Alexandra Bradu, David A Knowles, Rahul Satija.
      Single-cell perturbation dictionaries measure how cells respond to genetic and chemical perturbations, creating the opportunity to assign causal interpretations to observational data. We introduce RNA fingerprinting, a statistical framework that maps transcriptional responses from new experiments onto reference perturbation dictionaries. RNA fingerprinting learns perturbation representations, or "fingerprints," from single-cell data, then probabilistically assigns query cells to one or more candidate perturbations. We benchmark on ground-truth datasets, demonstrating accurate assignments at single-cell resolution, scalability to genome-wide screens, and the ability to resolve combinatorial perturbations. We demonstrate broad utility across diverse biological settings: identifying context-specific regulators of p53 under ribosomal stress, characterizing dose-dependent drug mechanisms of action, and uncovering cytokine-driven B cell heterogeneity during secondary influenza infection in vivo. Together, these results establish RNA fingerprinting as a versatile framework for interpreting single-cell datasets by linking cellular states to their underlying perturbations.
    Keywords:  Perturb-seq; computational biology; single-cell RNA-sequencing; statistical modeling
    DOI:  https://doi.org/10.1016/j.cell.2026.09.017
  2. Nat Commun. 2026 09 04. pii: 10520. [Epub ahead of print]17(1):
    Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism.
    Alba Fernández-Rodrigo, Celia García-Vilela, Abel Eraso-Pichot, Irene B Maroto, María D G Moreno, Esperanza López-Merino, Silvia Gutiérrez-Eisman, Carla Sánchez-Castillo, Cristina Boers-Escuder, Eneko Merino-Casamayor, Mariona Graupera, Albert Quintana, María I Cuartero, Maite Solas, Giovanni Marsicano, José A Esteban.
      Astrocytes modulate neuronal activity by gliotransmission and through metabolic regulation, yet the relationship between these functions remains poorly understood. Here we show that phosphatidylinositol 3-kinase (PI3K) signaling in astrocytes controls synaptic plasticity and memory by regulating cellular metabolism. Deletion of the p110α isoform of PI3K in hippocampal astrocytes impairs NMDA receptor activation during the induction of hippocampal long-term potentiation (LTP). This defect is rescued by either D-serine (co-agonist of synaptic NMDA receptors) or its precursor L-serine, indicating that PI3K regulates synaptic plasticity through serine availability. Indeed, deletion of p110α rewires astrocyte metabolism, reducing glycolytic flux while enhancing mitochondrial respiration. This, in turn, would limit L-serine biosynthesis through the phosphorylated pathway. Consistently, mice lacking astrocytic p110α display memory deficits that are rescued by in vivo L-serine administration. These findings identify astrocytic PI3K p110α as a key link between cellular metabolism, synaptic plasticity and cognition.
    DOI:  https://doi.org/10.1038/s41467-026-77319-0
  3. Nat Commun. 2026 Oct 09. pii: 10220. [Epub ahead of print]17(1):
    PI3Kδ is selectively inhibited by roginolisib by stabilizing the C-terminal helix kα12.
    Oscar Vadas, Simon Tiede, Maria Chaouki, Laura Tesmer, Shanlin Rao, Rémy Visentin, Ulrich Grädler, Martin Augustin, Reiner Kiefersauer, Carola Gößer, Anne Quillet-Mary, Loïc Ysebaert, Julie Guillermet-Guibert, Lars van der Veen, Giusy Di Conza, Gerhard Hummer.
      Phosphoinositide 3-kinases (PI3Ks) are major regulators of cell growth, proliferation and signalling, constituting key therapeutic targets in cancer, inflammation, and other diseases. Individual class I PI3K isoforms control key cellular functions, imposing the need to generate isoform-specific inhibition for therapeutic intervention. Roginolisib is a selective PI3Kδ inhibitor that shows promise for the treatment of cancer. Using a combination of X-ray crystallography, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, we describe the mechanism driving roginolisib's potent and isoform-selective inhibition of PI3Kδ. Roginolisib uniquely stabilises the catalytic C-terminal helix kα12, locking the enzyme in an inactive conformation. This binding mode also results in more sustained inhibition of phosphatidylinositol 3,4,5-trisphosphate formation in tumour samples of CLL patients. Inhibition of PI3Ks by stabilization of helix kα12 into an inactive conformation has not, to the best of our knowledge, been described before and may provide the basis for novel, more selective and effective pharmacological strategies.
    DOI:  https://doi.org/10.1038/s41467-026-77424-0
  4. bioRxiv. 2026 Aug 14. pii: 2026.08.13.744642. [Epub ahead of print]
    Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer.
    Johnvesly Basappa, Cosimo Lobello, Anneliese M Faustino, Cristina Uribe-Alvarez, David Rushmore, Niel Sen, Li Wang, Andrey Efimov, Kathy Q Cai, Jaime L Schneider, Lori Rink, Aaron N Hata, Luca Mologni, Wujuan Zhang, Aaron R Goldman, Hsin-Yao Tang, Reza Nejati, Roland Dunbrack, Jonathan Chernoff, Joseph A Baur, Mariusz A Wasik.
      Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage pathway, is frequently upregulated in cancer, yet mechanisms regulating its catalytic activity remain undefined. We identify NAMPT as a direct substrate of multiple proto-oncogenic tyrosine kinases, including ALK, insulin receptor, IGF1R, and PDGFRA. Phosphoproteomics identified NAMPT Y188 as the major phosphorylation site, including the oncogenic fusion kinase NPM1::ALK. NAMPT interacted with NPM1::ALK in the cytoplasm, nucleus, and mitochondria, while Y188 phosphorylation enhanced catalytic activity, NMN/NAD⁺ biosynthesis, and downstream metabolism. Conversely, the Y188F mutant reduced enzymatic activity, proliferation, and clonogenicity, whereas disrupting dimerization similarly impaired phosphorylation and function. Interactome analyses showed phosphorylation and dimerization cooperatively remodel NAMPT-associated networks, enriching phosphorylated dimers for metabolic/redox regulators and monomeric NAMPT for ribosome biogenesis. NAMPT inhibition suppressed the growth of both ALK inhibitor-sensitive and -resistant lymphoma cells and enhanced the efficacy of ALK inhibition, revealing kinase-dependent NAMPT activation as a metabolic vulnerability in oncogene-driven cancers.
    DOI:  https://doi.org/10.64898/2026.08.13.744642
  5. Npj Struct Biol. 2026 ;1(1): 1
    Mechanism of activation of an ancestral TEC kinase by PIP3.
    Eva Krötenheerdt, Lucas Piëch, Freia von Raußendorf, Ronja Reinhardt, Ranjana Nataraj, Nicholas Wedige, Hunter G Nyvall, Emma E Walsh, John E Burke, Thomas A Leonard.
      The TEC kinases are a family of five paralogous mammalian genes that play crucial roles in cell growth, proliferation, and differentiation, particularly in immune cells. The recruitment and activation of the TEC kinases depend on the generation of the lipid second messenger, PIP3, in the plasma membrane. However, the mechanisms by which PIP3 activates the TEC kinases are not well understood. By studying an ancestral TEC kinase from the choanoflagellate Monosiga brevicollis, we have elucidated an evolutionarily conserved mechanism for the activation of the TEC kinases by PIP3. We demonstrate that PIP3, but not PIP2, relieves autoinhibition by displacing the PH domain of MbTEC from a conserved intramolecular interaction with its kinase domain. We also show that a conserved polyproline motif within MbTEC promotes its activation in a kinase-intrinsic mechanism. Finally, we show that the PH domain is sufficient to restore autoinhibition in a constitutively active mutant of MbTEC. Our findings reveal that PIP3 is necessary but not sufficient for MbTEC activation.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1038/s44511-026-00001-z
  6. Mol Metab. 2026 Oct 06. pii: S2212-8778(26)00134-1. [Epub ahead of print] 102450
    PI3K is the dominant signalling pathway recruited by IRS proteins to mediate their effects on metabolism and growth.
    Steven J Millership, Nadia Tyler-Rubinstein, Elaine E Irvine, Marika Charalambous, Agharul I Choudhury, Santiago Vernia, Peter Voshol, Antonio Vidal Puig, Lazaros C Foukas, Dominic J Withers.
       OBJECTIVES: Insulin and Igf1 have pleiotropic effects on development, growth and metabolism. The activated insulin and IGF1 receptors engage insulin receptor substrate (IRS) proteins, intracellular adaptor molecules that recruit multiple downstream signalling pathways, including PI3K and GRB2-RAS-MAPK. Global deletion of IRS1 or IRS2 in mice results in divergent effects on growth, metabolism, and ageing. However, the precise signalling pathways recruited by IRS1 or IRS2 to mediate their physiological effects in vivo have not been defined.
    METHODS: We generated knock-in mice in which either IRS1 or IRS2 was mutated to prevent downstream recruitment of PI3K or GRB2 and undertook phenotypic analysis of these animals.
    RESULTS: Knock-in mice unable to recruit PI3K to IRS1 (Irs1YnF) or to IRS2 (Irs2YnF) had limited or no compensation in IRS2 and IRS1 signalling respectively. Irs1YnF mice were growth restricted, with reduced adiposity and insulin resistance, but did not develop diabetes due to compensatory increase in β-cell mass. Irs2YnF mice were obese and insulin resistant and developed diabetes due to β-cell failure. In contrast knock-in mice unable to recruit GRB2 to IRS1 (Irs1Y891F) or to IRS2 (Irs2Y911F) displayed normal growth and metabolism.
    CONCLUSIONS: PI3K recruitment by either IRS1 or IRS2 is the primary signalling mediator of the effects of these adaptor molecules on growth and metabolism in mice, and suggest that the other signalling pathways recruited by IRS1 and IRS2, including GRB2, have minimal or redundant roles.
    Keywords:  Diabetes; GRB2; Growth; IRS; Insulin; PI3K
    DOI:  https://doi.org/10.1016/j.molmet.2026.102450
  7. Exp Mol Med. 2026 Oct 07.
    Insulin mimetics and non-canonical insulin receptor signaling: mechanisms and disease relevance.
    Junhee Park, Eunhee Choi.
      Insulin receptor (IR) signaling has traditionally been viewed as a canonical pathway in which insulin binding uniformly activates downstream metabolic and mitogenic responses. However, growing evidence indicates that IR signaling is not monolithic. Instead, IR signaling is increasingly recognized as a context-dependent process in which receptor conformation, spatial organization, and intracellular trafficking shape signaling outcomes. These non-canonical regulatory mechanisms generate distinct signaling states that can differentially regulate metabolic, mitogenic, immune, and neuronal functions. Recent advances in engineered insulin mimetics, including peptides, antibodies, aptamers, and de novo designed ligands, have provided powerful tools to probe this signaling diversity. By stabilizing specific receptor conformations or engagement geometries, these ligands can selectively bias downstream signaling programs. Here we discuss recent insights into how the qualitative features of IR signaling, rather than signaling amplitude alone, determine disease outcomes across diverse pathological contexts. Understanding this signaling diversity may enable the rational design of next-generation insulin mimetics and more precise therapeutic strategies targeting IR pathways.
    DOI:  https://doi.org/10.1038/s12276-026-01862-5
  8. Acta Physiol (Oxf). 2026 Nov;242(11): e70325
    Klotho Deficiency Impairs Distal Potassium Homeostasis Through mTORC1-Dependent Suppression of ROMK.
    Wakako Kawarazaki, Nobuhiro Ayuzawa, Mitsuhiro Nishimoto, Daigoro Hirohama, Kohei Ueda, Takeshi Marumo, Toshiro Fujita.
       AIM: Hyperkalemia is prevalent in the elderly, and underlying molecular mechanisms remain incompletely understood. We hypothesized that Klotho deficiency, a feature of aging, impairs renal potassium homeostasis and contributes to hyperkalemia.
    METHODS: Klotho heterozygous knockout (KLhet) mice, characterized by reduced Klotho levels, were used to investigate determinants of potassium handling, including renal outer medullary potassium channel (ROMK)1, the epithelial sodium channel (ENaC), which provides the driving force for ROMK-mediated potassium secretion, and plasma aldosterone concentration (PAC).
    RESULTS: KLhet mice developed hyperkalemia with reduced urinary potassium excretion, accompanied by activation of renal mechanistic target of rapamycin complex 1 (mTORC1) signaling, indicated by increased phosphorylated S6, and decreased ROMK1 abundance in the plasma membrane fraction. Adrenal expression of aldosterone synthase Cyp11b2 and PAC were elevated, and ENaC activity was enhanced, as evidenced by increased cleavage of α- and γ-ENaC subunits, partially compensating for impaired potassium excretion. Pharmacological ENaC inhibition with amiloride precipitated severe hyperkalemia in KLhet mice. In contrast, treatment with the mTORC1 inhibitor rapamycin or Klotho supplementation suppressed renal mTORC1 signaling, restored plasma membrane ROMK1 abundance, increased urinary potassium excretion, and normalized serum potassium levels, with reduced Cyp11b2 expression.
    CONCLUSION: Klotho deficiency impairs renal potassium handling through mTORC1-dependent downregulation of ROMK, with compensatory hyperaldosteronism and ENaC activation. These findings highlight an important role of the Klotho-mTORC1 axis in distal potassium homeostasis and its potential as a therapeutic target for Klotho deficiency-associated hyperkalemia.
    Keywords:  Klotho; ROMK; aldosterone; distal nephron; hyperkalemia; mTORC1; renin–angiotensin system
    DOI:  https://doi.org/10.1111/apha.70325
  9. J Thromb Haemost. 2026 Oct 03. pii: S1538-7836(26)00624-0. [Epub ahead of print]
    Coactivators YAP and TAZ Contribute Differently to the Transcriptional Regulation of VWF in Endothelial Cells.
    Meaghan O'Donnell, Anthony Guglya, Elham Ghorbanpour, Nathalie Tijet, Colleen Notley, Emily Bucciol, Taha Azad, Helena Janse van Rensburg, Xiaolong Yang, David Lillicrap.
       BACKGROUND: Upstream signals and associated signalling axes that contribute to the differential VWF expression observed across various vascular beds remain unclear. Transcriptional coactivators YAP and TAZ, through transcription factors including TEAD, may contribute distinctly to this heterogeneity in response to external mechanical stimuli.
    OBJECTIVES: Investigate the role of YAP/TAZ in the transcriptional regulation of VWF in endothelial cells (ECs).
    METHODS: Human umbilical vein ECs (HUVECs) and human aortic ECs (HAECs) were assessed for levels of VWF mRNA and VWF:Ag following YAP/TAZ gene silencing by siRNA. VWF promoter activity was measured in HUVECs using luciferase reporter constructs, both before and after inactivating the promoter's single TEAD site. Changes in VWF mRNA and VWF:Ag were measured in ECs exposed to shear stress (5-30 dynes/cm2), and immunofluorescent microscopy was used to visualise and quantify intracellular TAZ localisation.
    RESULTS: YAP and TAZ assumed different roles between EC subtypes. In HUVECs, we observed a TAZ-dominant contribution to VWF expression across siRNA and shear stress experiments. In HAECs, our results are consistent with a negative regulatory role of YAP on TAZ. Modifications to the TEAD sequence reduced VWF expression in HUVECs, indicating mechanistic convergence of YAP/TAZ on this site, further supported by chromatin immunoprecipitation (ChIP) and in silico ChIP-seq analysis. Immunocytochemistry displayed cytoplasmic TAZ localisation under high laminar flow, implicating shear stress as a negative regulator of VWF expression.
    CONCLUSION: YAP and TAZ are novel contributors to the transcriptional regulation of VWF in ECs through a TEAD-dependent mechanism, acting independently and distinctly in various EC subtypes.
    Keywords:  Cellular Mechanotransduction; Mechanical Stress; TAZ-Signaling Proteins; Von Willebrand Factor; YAP-Signaling Proteins
    DOI:  https://doi.org/10.1016/j.jtha.2026.09.034
  10. Cell. 2026 Oct 08. pii: S0092-8674(26)01196-7. [Epub ahead of print]
    Comprehensive lineage tracing maps the landscape of cell fate decisions in mouse embryogenesis.
    William N Colgan, Luke W Koblan, JoAnne Villagrana, Tien-Chi Jason Hou, Minming Wang, Gokul Gowri, Whitney Chandler, Leonardo A Sepúlveda, Didar Ciftci, Karina Smolyar, Kathryn E Yost, Alicia Young, Lars Wittler, Styliani Markoulaki, Kyle M Loh, Xiaowei Zhuang, Nir Yosef, Zachary D Smith, Jonathan S Weissman.
      A comprehensive cell fate map of mammalian embryogenesis has remained out of reach given the scale, cellular diversity, and non-deterministic nature of development in utero. Here, we use PEtracer to continuously install heritable genetic marks as development progresses, reconstructing lineage trees that resolve ∼75% of cell divisions across >1.4 million cells from 16 replicate embryos. We pair these trees with deep transcriptional profiling to resolve cell fate biases, restriction timing, progenitor pool sizes, and lineage relationships throughout embryogenesis. Using this quantitative reference, we uncover strikingly reproducible lineage architecture between replicate embryos and chart the lineage dynamics driving fate specification across diverse tissues. Specific biological insights include the progressive restriction of neural crest fate, the relative contributions of distinct mesodermal origins to endothelium, and the dynamics of axial elongation. This work provides a foundation for a quantitative and predictive understanding of mammalian development.
    Keywords:  PEtracer; cell fate specification; lineage tracing; mouse embryogenesis; scRNA-seq; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.cell.2026.09.050
  11. Science. 2026 Oct 08. eael0508
    A DNA Typewriter records the cell lineage history of a mouse, from zygote to late organogenesis.
    Qi Yu, Haedong Kim, Sophie Seidel, James F Acosta-Clark, Beth K Martin, Kyle O'Connor, Riza M Daza, Molly Gasperini, Jenny F Nathans, Maggie Lam, Elena Gamo, Shruthi Vijay Kumar, Lauren Kuo, Jean-Benoît Lalanne, Kamen P Simeonov, Marion Pepper, Cole Trapnell, Jesse M Gray, Junhong Choi, Chengxiang Qiu, Jay Shendure.
      Mammalian biology unfolds over time, within tissues and organs opaque to our eyes and instruments. We applied DNA Typewriter, a sequential molecular recorder, to record the cell lineage of a mouse over nearly two weeks of development. From one embryo, we reconstruct a time-calibrated, parsimony-supported, zygote-rooted phylogeny of 1.28 million transcriptionally profiled cells. A burst of editing unequivocally marks the daughters of the first cleavage, which serve as inline replicates. We quantify clonal dominance arising during gastrulation. Tree siblings share cell type far above chance; heterotypic siblings mark terminal differentiations. Temporal sweeps of clade co-occurrence recover a dated hierarchy of cell-type couplings; imputed labels for internal nodes recapitulate known state paths. A lineage-anchored ontogeny of mammalian development, long out of reach, is coming into view.
    DOI:  https://doi.org/10.1126/science.ael0508
  12. PLoS Genet. 2026 Oct 08. 22(10): e1012330
    Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling.
    Vinoth Sigamani, Mohd Yousuf, Daniel L Johnson, Brian D Strahl, R Nicholas Laribee.
      Chromatin is dynamically regulated in response to nutrient flux to promote the transcriptional changes needed for adaptation. The mechanistic target of rapamycin complex 1 (yeast TORC1) kinase integrates nutrient signaling with chromatin regulation, yet whether chromatin signals back to regulate TORC1 remains unclear. We find that a histone H3 lysine 37 to alanine (H3K37A) mutant predicted to disrupt a histone-DNA contact promotes histone degradation, hyperactivates TORC1, and causes cytotoxicity upon TORC1 inhibition. This cytotoxicity is specific to H3K37A, since chromatin instability in wild-type histone H3 (H3WT) cells reduces histone abundance and hyperactivates TORC1 without cytotoxicity upon TORC1 inhibition. Combining H3K37A with these chromatin stability mutants exacerbates histone loss, TORC1 hyperactivity, and lethality during TORC1 inhibition. Transcriptome analysis indicates H3K37A deregulates mitochondrial retrograde signaling, which is exacerbated upon TORC1 inhibition and becomes cytotoxic due in part to defective mitochondrial import of an OXPHOS subunit. Retrograde inactivation, or neutralization of reactive oxygen species (ROS) prevents this toxicity. These findings identify chromatin stability as an upstream restraint on TORC1 signaling, revealing bidirectional communication between chromatin and a major nutrient-responsive pathway. They further show H3K37 has an additional functionality that prevents mitochondrial dysregulation during metabolic stress adaptation.
    DOI:  https://doi.org/10.1371/journal.pgen.1012330
  13. Commun Biol. 2026 Oct 07. pii: 1304. [Epub ahead of print]9(1):
    ESR1 mutations are associated with enhanced MTORC1 signaling in a context-dependent manner.
    Tommaso De Marchi, Magdalena Kuras, Lazaro Hiram Betancourt, Sven Kjellström, Jeanette Valcich, Johan Vallon-Christersson, Christian Brueffer, Lao H Saal, Johan Malmström, Emma Niméus.
      ESR1 mutations are a driver of endocrine therapy resistance in breast cancer, however their impact on protein signaling pathways and clinical outcomes remains poorly understood. We analyzed the transcriptomic, proteomic, and phosphoproteomic landscape of tumors harboring ESR1 mutations. Here we show that ESR1 mutated cancers exhibit a higher mutational burden associated with increased cell proliferation, and display enhanced activation of the mTOR pathway via MTORC1, suggesting an ER-driven amplification of existing oncogenic mechanisms. Analysis of an independent proteomic dataset from breast cancer cell lines further supported a convergence between MTORC1 and ER signaling programs. Integrative multi-omic data analysis incorporating features related to tumor grade, MTORC1 signaling, and ESR1 mutations, enabled the development of a predictive signature that distinguishes patients with ESR1 mutation and identified those at high risk of recurrence. This study provides insights into the mechanisms underlying tumor aggressiveness and poor clinical outcome modulated by ESR1 mutations and highlights the potential of proteogenomic approaches to identify signaling pathways and molecular signatures.
    DOI:  https://doi.org/10.1038/s42003-026-11096-w
  14. Development. 2026 Oct 07. pii: dev.205569. [Epub ahead of print]
    Mastodon: the command center for large-scale lineage-tracing microscopy datasets.
    Johannes Girstmair, Tobias Pietzsch, Vladimir Ulman, Stefan Hahmann, Matthias Arzt, Mette Handberg-Thorsager, Samuel Pantze, Ko Sugawara, Robert Haase, Shuichi Onami, Jean-Yves Tinevez, Pavel Tomancak.
      Understanding development in living organisms requires following the divisions, movements, and fates of cells. While advances in microscopy have enabled whole-embryo imaging at the cellular level, extracting and analyzing cell lineages from these massive datasets remains a significant computational challenge. We present Mastodon, a scalable, extensible software platform for manual, semi-automated, and automated cell tracking in large images. A purpose-built graph model supports responsive performance for datasets with millions of annotations, making Mastodon a scalable platform for cell lineage analysis. Built as a Fiji plugin, Mastodon enables interactive visualization, editing, and analysis of complex lineage trees, seamlessly integrated with the raw image data. Comprehension of cell lineages in complex three-dimensional geometries is facilitated by interoperability with the powerful open-source render engine Blender. In three distinct developmental contexts, we demonstrate how Mastodon will accelerate biological insights by providing user-friendly navigation and explorative analysis in complex lineage datasets.
    Keywords:  Annotation and visualisation; Big image data analysis; Cell tracking; Embryonic development; Lineage reconstruction; Open source software
    DOI:  https://doi.org/10.1242/dev.205569
  15. Cell. 2026 Oct 08. pii: S0092-8674(26)01203-1. [Epub ahead of print]
    A fluctuation test for gastruloid heterogeneity.
    Samuel G Regalado, Chengxiang Qiu, Sanjay Kottapalli, Chau Huynh, Riza M Daza, Aidan Keith, Jihye Park, Beth K Martin, Wei Chen, Hanna Liao, Haedong Kim, Xiaoyi Li, Jean-Benoît Lalanne, Nobuhiko Hamazaki, Silvia Domcke, Junhong Choi, Jay Shendure.
      Stem cells self-organize into models of early development, but even under carefully controlled conditions, the resulting organoids exhibit substantial "inter-individual" heterogeneity. To explore its origins, we generated monoclonal gastruloids, each derived from a single mouse embryonic stem cell (mESC). Molecular profiling revealed extensive heterogeneity: some gastruloids failed to develop, others were biased toward mesodermal or neural fates, and yet others contained cell types atypical of conventional polyclonal gastruloids. Applying DNA Typewriter, a cell lineage recorder, we identified heritable fate biases arising prior to gastruloid induction and found that more closely related founder mESCs give rise to more phenotypically similar gastruloids. Linking mESC subclones to their descendants' fates revealed cryptic, fate-predictive differences in gene expression and chromatin accessibility, including at imprinted, methylation-sensitive loci linked to developmental potency. Intrinsic, heritable fluctuations in mESC state are therefore an important source of organoid heterogeneity, and DNA Typewriter enables high-resolution lineage trees in stem cell models.
    Keywords:  Tet1; cellular memory; clonal tracking; gastruloid; heterogeneity; lineage recording; molecular recording; mouse embryonic stem cell; multiomics; organoid
    DOI:  https://doi.org/10.1016/j.cell.2026.09.057
  16. Nat Commun. 2026 Oct 09. pii: 10219. [Epub ahead of print]17(1):
    The conformation-selective PI3Kδ inhibitor roginolisib in patients with advanced or metastatic cancer, including metastatic uveal melanoma: first-in-human clinical trial.
    Anna Maria Di Giacomo, Matteo Simonelli, Agnese Losurdo, Pavlina Spiliopoulou, Vincenzo D'Alonzo, Giovanni Amato, Monica Valente, Hugo Barcenilla, Anette Johnsson, Laura Gonzalez, Ziyang Tan, Lakshmikanth Tadepally, Petter Brodin, Michael Lahn, Giusy Di Conza, Rebeca Zorrilla, Lars van der Veen, Alessio Bevilacqua, Paramjit Kaur, Tracey Hammett, Marco Durini, Andrea Corsi, Nikhil Sindhwani, Mariaelena Occhipinti, Robert Snijder, Ayad Abdul-Ahad, Aniko Meijer, Umberto Postiglione, Gregory Price, Gillian Hopton, Emily Wood, Vincent Vuaroqueaux, Anne-Lise Peille, Jill Graham, Ming Poi, David Spetzler, Carmelo Carlo-Stella, Armando Santoro, Thomas R Jeffry Evans, Michele Maio.
      Phosphatidylinositol 3-kinase delta (PI3Kδ) promotes tumour cell growth directly or indirectly by activating immune-suppressive cells. In contrast to previous PI3Kδ inhibitors, roginolisib is a selective, non-ATP competitive inhibitor, which locks PI3Kδ into an inactive state and causes an allosteric modulation. In a First-in-Human dose study, continuous daily dosing of roginolisib was investigated in patients with solid and haematologic malignancies. In Part A, 24 patients received escalating doses of roginolisib. In Part B, 20 mostly pre-treated metastatic uveal melanoma (mUM) patients received a dose associated with continuous PI3Kδ inhibition of >90%. The primary endpoint was safety, and secondary endpoints included pharmacokinetic (PK) and pharmacodynamic (PD) profile, clinical anti-tumour responses assessments. Exploratory endpoints included immunophenotyping, proteomics, genomics. No Dose Limiting Toxicity or drug related toxicities requiring dose modifications were observed ( ≥ Grade 3 toxicities: 3/44; 6.8%). In mUM, median Overall Survival (mOS) was 20.8 months (data-cut off December 2023) and 18.4 months (data-cut-off February 2026). mOS in mUM patients with Stable Disease at Week 16 ( = Cycle 5) was 28.5 months, while patients who progressed at Week 16 had a median OS of 12.3 months. Roginolisib was safe, had a predictable PK profile, T regulatory cell abundance was decreased while activated CD8+ T cells increased together with soluble plasma IL-15. ClinicalTrials.gov registration: NCT04328844.
    DOI:  https://doi.org/10.1038/s41467-026-77358-7
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