bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2026–10–25
fifteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Cooperative Membrane Recognition by Lipid-Sensing and Kinase Domains Shapes Membrane-Bound States of AKT.
  2. Loss of intestinal Akt elicits rapid mortality via intestinal damage which is rescued by mTORC1 activation.
  3. Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300.
  4. Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis.
  5. Phosphorylation of IRS4 at YY111/112 promotes LUSC progression via PI3K/AKT pathway activation.
  6. The kinase inhibitor dabrafenib halts progression of cerebral cavernous malformations in a BRAF-independent manner.
  7. Rapalink-1 reveals an mTOR- and p53-regulated transcriptional program in Neuro-2a cells.
  8. IGFBP5 derived from endothelial cells drive vascular invasion and liver metastasis of colorectal cancer by activating the ITGB3/PI3K/AKT Axis.
  9. OpenDVP: an experimental and computational framework for community-empowered deep visual proteomics.
  10. Molecular-genetic mechanisms of cerebral arteriovenous malformations: A systematic review of germline, somatic and experimental evidence.
  11. ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes.
  12. Multiscale modeling reveals non-linear dynamics of AKT-mediated NO-ROS crosstalk in shear stress-induced endothelial phenotype.
  13. Asymmetric crosstalk between the BMP and TGF-β pathways resolves signaling ambiguity.
  14. Tissue coordination in ageing and disease.
  15. Defining early human developmental identity: A curated, cross-platform marker framework.
  1. J Am Chem Soc. 2026 Oct 14. 148(40): 43423-43432
    Cooperative Membrane Recognition by Lipid-Sensing and Kinase Domains Shapes Membrane-Bound States of AKT.
    Yuki Nakagaki, Toshiki Mori, Kenichi G N Suzuki, Eiji Yamamoto.
      The PI3K/AKT signaling pathway is triggered by the recruitment of AKT to cellular membranes. Although AKT is a multidomain serine/threonine kinase composed of an N-terminal pleckstrin homology (PH) domain and a C-terminal kinase domain (KD), how these domains cooperate to regulate AKT activation on membranes remains unclear at the molecular level. Here, using molecular dynamics simulations of full-length AKT on phosphatidylinositol (3,4,5)-trisphosphate (PIP3)-containing lipid bilayers, we identify four distinct membrane-binding modes that differ in the orientations and membrane contacts of the PH domain and KD. In addition to PIP3 binding to the PH domain, we observed specific PIP3 interactions with basic residues in the KD. In the most stable mode, PIP3 interacts with both the canonical and a secondary binding site in the PH domain, while the KD adopts an orientation in which the activation loop phosphorylation site is exposed to the solvent. The populations of these binding modes depend on the PIP3 concentration in the membrane, leading to changes in the preferred orientation of AKT. Live-cell single-molecule imaging further supports distinct but cooperative roles of the PH domain and KD in membrane recruitment: the PH domain primarily promotes membrane association, whereas the KD enhances recruitment efficiency and stabilizes longer-residence membrane-bound states. These findings suggest that AKT membrane recruitment is governed by cooperative contributions from both the PH domain and the KD, providing molecular insight into how AKT is positioned and stabilized on PIP3-containing membranes.
    DOI:  https://doi.org/10.1021/jacs.6c13162
  2. Nat Commun. 2026 Sep 23. pii: 11057. [Epub ahead of print]17(1):
    Loss of intestinal Akt elicits rapid mortality via intestinal damage which is rescued by mTORC1 activation.
    Ahmed Magdy, Hyunsoo Rho, Muzamil Mushtaq, William Putzbach, Veronique Nogueira, Vaibhav Chand, Nissim Hay.
      Combined Akt1 and Akt2 systemic deletion in adult mice elicits rapid mortality, preceded by body weight loss, diarrhea, and inflammation. Here, we show that lethality induced by systemic Akt1/Akt2 deletion is caused by intestinal damage, as intestinal Akt1/Akt2 deletion induces mortality phenocopying systemic deletion. Consistently, Akt ablation impairs intestinal organoid formation in vitro. Both in vivo and in vitro results show that Akt is essential for the survival of Paneth cells and survival and proliferation of Lgr5+ and transit-amplifying cells. Additional intestinal deletion of either FoxO1 or Tsc1 activates mTORC1 and rescues this phenotype. Thus, mTORC1 emerges as the most critical downstream effector of Akt in maintaining intestinal integrity. Indeed, mTORC1 inhibition by Raptor deletion phenocopies intestinal deletion of Akt1/Akt2. Remarkably, systemic Akt1/Akt2 deletion is tolerated when FoxO1 is deleted concurrently. This study unravels a critical role for Akt in maintaining intestinal homeostasis and the interplay between its downstream effectors FoxO1 and mTORC1.
    DOI:  https://doi.org/10.1038/s41467-026-77283-9
  3. J Exp Med. 2026 Nov 02. pii: e20251898. [Epub ahead of print]223(11):
    Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300.
    Ian M Delahunty, Stephanie Nance, Yang Zhang, Francois Lamoureux, Qi Liu, William C Wright, K Elaine Ritter, Noha A M Shendy, Bénédicte Brounais-Le Roye, Sandra J Kietlinska, Mohammad A Mohammad Nezhady, Yuan Feng, Barbara De Kegel, Matthew G Rees, Mustafa Kocak, Ashish B George, Meifen Lu, Anoop M Kavirayani, Bo Wang, Yanling Liu, Paris E A Prinsen, Yousef Khashana, Vernon Justice Ebegboni, Melissa M Ronan, Jennifer A Roth, E Alejandro Sweet-Cordero, Lillian M Guenther, Paul Geeleher, Xiaotu Ma, Benjamin Ory, Jun Qi, Brian J Abraham, Adam D Durbin.
      Cancers depend on transcriptional control to maintain the malignant cell state. EP300 and CBP are paralogous master epigenetic enzymes that control normal and malignant transcription. Using a cancer-wide integrative chemical-genetic analysis, we demonstrate enhanced dependency on EP300, compared with CBP, in cell lines from most cancer lineages, including lethal osteosarcoma (OS). Using a selective EP300 degrader (JQAD1), we identify that a genetically defined subgroup of OS with dysregulation of the PI3K-AKT-mTOR pathway is genetically and chemically sensitive to loss of EP300. Activated AKT promotes sensitivity to JQAD1, driven by relocalization of EP300, CBP and H3K27ac to genetic subtype-enriched dependency loci. AKT inhibition combines with JQAD1 to synergistically suppress the growth of AKT-dysregulated OS cells in vitro and in orthotopic xenografts. These observations extend across >850 cancer cell lines, where synergy is predicted by elevated protein synthetic rates. These findings reveal determinants of EP300 degrader function in OS and provide a foundation for co-targeting EP300 and AKT in cancers with enhanced protein translation.
    DOI:  https://doi.org/10.1084/jem.20251898
  4. Nat Aging. 2026 Oct 23.
    Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis.
    Sarah Dobner, Lisa Kleissl, Fanni Tóth, Robert L Paxton, Irena Yordanova, Kveta Brazdilova, Cedric Vanluyten, Aleksandra Aizenshtadt, Hanna Tóth, Jake Burton, Aglaja Kopf, Vera Belyaeva, Katharina Ferencevic, Dunja A Al-Nuaimi, Mauriz A Lichtenstein, Georg E Winter, André F Rendeiro, Christoph Bock, Joanna Kalucka, Stefan Krauss, Selma Osmanagic-Myers, Laurens J Ceulemans, Georg Stary, Abdel Rahman Abdel Fattah, Laura P M H de Rooij.
      Endothelial cells (ECs) are critical regulators of vascular function and exhibit tissue-specialized roles. During aging, these cells become dysfunctional, resulting in increased susceptibility to cardiovascular disease. Although single-cell transcriptomics has revealed extensive endothelial heterogeneity, a comprehensive atlas of human EC transcriptomes over the course of the adult human lifespan has been lacking. Here, we present the Human Aging Endothelial Cell Atlas (HAECA), a harmonized single-cell transcriptomic compendium of over 375,000 ECs from 12 human tissues throughout adulthood. We identified age-associated transcriptional shifts, including a decline in angiogenic gene expression in venous ECs and widespread alterations in extracellular matrix and mechanotransduction-associated signatures. Furthermore, we uncovered a p21-linked transcriptional program in ECs, which we linked to cellular senescence in both in vitro and in vivo models. Together, our study provides a high-resolution transcriptomic reference of the human endothelium across tissues and age.
    DOI:  https://doi.org/10.1038/s43587-026-01247-3
  5. Oncogene. 2026 Oct 17.
    Phosphorylation of IRS4 at YY111/112 promotes LUSC progression via PI3K/AKT pathway activation.
    Yilixiati Aihemaiti, Qiuhan Ren, Xiangling Jiang, Kaideya Wushaying, Ran Chen, Yanli Wang, Xian Zhao, Lei Xu, Zhi Yang, Jianxiu Yu, Jian Huang.
      Lung squamous cell carcinoma (LUSC) lacks effective targeted therapies despite frequent hyperactivation of the PI3K/AKT pathway, and the contribution of adaptor proteins to this process remains poorly defined. Here, we identify Insulin Receptor Substrate 4 (IRS4) as a common substrate of Src kinase and the phosphatase RPTPα, and uncover a previously unrecognized, conserved phosphorylation site at YY111/112 within the IRS4 PH domain. Src-mediated phosphorylation at this site is essential for IRS4-driven proliferation, anchorage-independent growth, and invasiveness in LUSC cells. Mechanistically, phosphorylation at YY111/112 induces conformational rearrangements in IRS4 that enhance the recruitment of the p85β SH2 domain to the YXXM motif of IRS4, thereby promoting AKT activation without altering IRS4 protein stability or subcellular distribution. An IRS4-derived cell-permeable phosphopeptide containing pYY111/112 disrupts the Src-IRS4 interaction and significantly suppresses tumor growth in vivo in a YY111/112-dependent manner. Consistently, YY111/112 phosphorylation is markedly elevated in human LUSC tissues and correlates with advanced disease stages. Collectively, these findings define a Src-IRS4-PI3K/AKT signaling axis and identify YY111/112 as a critical regulatory site of IRS4 and a potential therapeutic vulnerability in LUSC.
    DOI:  https://doi.org/10.1038/s41388-026-04015-0
  6. Sci Transl Med. 2026 Oct 21. 18(872): eadr0448
    The kinase inhibitor dabrafenib halts progression of cerebral cavernous malformations in a BRAF-independent manner.
    Maximiliano Arce, Hua Huang, Charlotte Rorsman, Iza Erzar, Joppe Oldenburg, Ying Sun, Ross Smith, Favour C Onyeogaziri, Stefano Barbera, Frida C Ahlstrand, Petter Ranefall, Anna Klemm, Mark Richards, Anna Dimberg, Lena Claesson-Welsh, Peetra U Magnusson.
      Cerebral cavernous malformations (CCMs) constitute the second most common type of intracranial vascular malformations. Cavernomas arise because of somatic or autosomal dominant inherited loss-of-function mutations in CCM genes, forming fragile mulberry-like malformed blood vessel structures that are prone to leak and break. Treatment is limited to surgical removal of solitary cavernomas, and because patients often present with multiple lesions, pharmacological alternatives to surgery are needed. We performed a high-throughput screen of 5200 bioactive molecules in programmed cell death 10 (PDCD10 or CCM3)-deficient mouse endothelial cells, coupled to automated image analysis. This screen identified dabrafenib, a clinically approved BRAF inhibitor, as a compound that restored cell-cell junctions and vascular barrier properties of CCM3-deficient endothelial cells. The potential translatability of dabrafenib was tested in acute and chronic CCM mouse models, where it reduced cerebral lesion burden and suppressed lesion permeability. Dabrafenib also rescued abnormal structural defects present in the developing retina vasculature in an acute CCM mouse model. Mechanistically, dabrafenib targeted extracellular regulated kinase (ERK)5-Krüppel-like factor (KLF)2/4 signaling and suppressed F-actin stress fiber formation in human brain endothelial cells, two potentially independent and central molecular processes involved in CCM pathology. Silencing BRAF did not prevent dabrafenib-induced KLF2/4 inhibition or restoration of cell-cell junctions, suggesting that its dual therapeutic outcome is independent of BRAF pathway inhibition. In conclusion, dabrafenib is a low-molecular weight compound that inhibits cavernoma pathogenesis, suggesting that CCMs could be treated with dabrafenib to block cavernoma growth and vascular leakage.
    DOI:  https://doi.org/10.1126/scitranslmed.adr0448
  7. Biol Open. 2026 Oct 15. pii: bio062902. [Epub ahead of print]15(10):
    Rapalink-1 reveals an mTOR- and p53-regulated transcriptional program in Neuro-2a cells.
    Joel Karikari Nyarkoh, Matthew Wolan, Eric Barrett, Aidan M Sokolov, Rachel A Lyman, Trudy F C Mackay, David M Feliciano.
      The mammalian target of rapamycin (mTOR) is the catalytic subunit of two exclusive complexes referred to as mTORC1 and mTORC2. The mTORCs phosphorylate different substrates and control different cellular processes. Inhibitors of mTORC1 include rapamycin analogs (rapalogs) that are useful in many clinical settings. However, they have failed in cancer trials potentially due to resistance mechanisms and incomplete inhibition of mTORC1 phosphorylation of select substrates. The rapamycin sensitivity of mTORC1 substrates is likely encoded by the substrate's primary amino acid sequence determinants and the ability of substrates to fit into the catalytic region of the kinase super-complex. Thus, some mTORC1 substrates are unaffected by rapalogs. Second-generation ATP-binding pocket inhibitors are mTOR catalytic inhibitors that bind in an ATP-competitive manner. Torin1 is an exemplary second-generation mTOR inhibitor with superior inhibition of mTORC1 substrates, including 4EBP. However, these inhibitors fail to demonstrate selectivity between mTORC1 and mTORC2. Third-generation bisteric mTORC1 inhibitors are exemplified by Rapalink-1, which links a rapamycin moiety to the ATP-competitive inhibitor MLN-0128. Here, we report that Rapalink-1 inhibits three mTORC1 substrates, including 4EBP and Ulk1, which are rapamycin insensitive. To provide additional mechanistic insight into the Rapalink-1 mechanism of action, RNA sequencing of Neuro-2a cells treated with Rapalink-1 was performed. Rapalink-1 caused transcriptomic changes indicative of reductions in the mTOR pathway and brain development. Many transcripts contained a p53 binding site, and consistent with this finding, we also observed reduced levels of p53. These results confirm and expand upon the Rapalink-1 mechanism of action.
    Keywords:  Cancer; Rapalink-1; mTOR; mTORC1
    DOI:  https://doi.org/10.1242/bio.062902
  8. Cell Death Dis. 2026 Jul 23. pii: 891. [Epub ahead of print]17(1):
    IGFBP5 derived from endothelial cells drive vascular invasion and liver metastasis of colorectal cancer by activating the ITGB3/PI3K/AKT Axis.
    Nuersimanguli Maimaitiming, Yiqiao Deng, Huayuan Liu, Junshuai Xue, Chengyao Guo, Xiaomeng Liu, Bingzhi Wang, Xiao Chen, Zhen Huang, Hong Zhao, Jianqiang Cai.
      Vascular invasion (VascI) is a critical step in colorectal cancer (CRC) metastasis, but how specific cells in the tumor microenvironment (TME) regulate this process remains unclear, particularly the role of endothelial cells (ECs). Here, we found that vascular invasion is strongly associated with distant metastasis and poor prognosis in CRC patients. Analysis of single-cell RNA sequencing (scRNA-seq) data from 8 colorectal cancer liver metastases (CRLMs), included 4 VascI+ CRLMs and 4 VascI- CRLMs, and identified 10 distinct EC subpopulations. Notably, an IGFBP5_tipECs significantly enriched in VascI+ CRLMs. High IGFBP5 expression correlated with VascI+ status and poor patient prognosis. Functionally, IGFBP5 overexpression (OE) in human umbilical vein endothelial cells (HUVECs) enhanced EC migration, tube formation, barrier disruption, and endothelial-to-mesenchymal transition (EndMT). In co-culture system, IGFBP5-OE ECs promoted malignant epithelial cells (MCs) proliferation, migration, and adhesion, and accelerated the growth of patient-derived CRC organoids. Mechanistically, RNA sequencing nominated ITGB3 as a key downstream effector, with activation of the PI3K/AKT signaling pathway. We confirmed a direct ligand-receptor interaction between EC-derived IGFBP5 and ITGB3 on MCs using multiplex immunofluorescence (mIF), co-immunoprecipitation (Co-IP), and proximity ligation assays (PLA). This interaction activated PI3K/AKT signaling in MCs, driving aggressive behavior both in vitro and in vivo, an effect that was significantly attenuated by ITGB3 silencing in MCs. Our findings identify IGFBP5-OE ECs as a key driver of VascI and liver metastasis in CRC via the ITGB3/PI3K/AKT axis, highlighting a potential therapeutic target to suppress metastatic progression.
    DOI:  https://doi.org/10.1038/s41419-026-09081-6
  9. Nat Methods. 2026 Oct 22.
    OpenDVP: an experimental and computational framework for community-empowered deep visual proteomics.
    Jose Nimo, Sonja Fritzsche, Daniela S Valdes, Minh Trinh, Tancredi Pentimalli, Melissa Klingeberg, Simon Schallenberg, Frederick Klauschen, Florian Herse, Stefan Florian, Nikolaus Rajewsky, Fabian Coscia.
      Deep visual proteomics (DVP) is an emerging approach for cell-type-specific and spatially resolved proteomics. However, its broad adoption has been constrained by the lack of an open-source end-to-end workflow within a community-driven ecosystem. Here we introduce openDVP, an experimental and computational framework for accessible and scalable DVP. OpenDVP combines open-source image analysis tools (MCMICRO, QuPath and napari) with scverse formats (AnnData and SpatialData) for multiomics integration. It provides two workflows: a fast-track pipeline requiring no image analysis expertise, and an artificial intelligence-powered pipeline incorporating state-of-the-art methods for image preprocessing, segmentation and spatial analysis. We apply openDVP across three archival tissue studies (human placenta, early stage lung cancer and locally relapsed breast cancer), integrating spatial single-cell phenotypes with exploratory proteomic measurements. Finally, we introduce deep proteomic profiling of cellular neighborhoods as a scalable approach for spatial discovery proteomics.
    DOI:  https://doi.org/10.1038/s41592-026-03262-z
  10. Neurosurg Rev. 2026 Oct 22. pii: 622. [Epub ahead of print]49(1):
    Molecular-genetic mechanisms of cerebral arteriovenous malformations: A systematic review of germline, somatic and experimental evidence.
    Anton Konovalov, Fyodor Grebenev, Yuri Pilipenko, Dmitry Okishev, Olga Belousova, Galina Pavlova, Shalva Eliava, Daria Starostenko, Anton Artemyev, Sofia Sergeeva, Ivan Erokhin.
      Cerebral arteriovenous malformations (AVMs) are high-flow vascular anomalies that carry a considerable burden of haemorrhagic morbidity. Work over the past decade has shown that both inherited syndromes and apparently sporadic lesions can be traced to alterations in a handful of signalling pathways, but the relevant evidence sits awkwardly between human genetic studies, animal models, and molecular profiling experiments. To bring together the current evidence on the molecular and genetic underpinnings of cerebral AVM formation, clinical course, and candidate therapeutic targets. We searched MEDLINE (PubMed), Embase, Web of Science Core Collection, and Scopus from inception to 1 January 2026. Records were screened, and full texts assessed, by two reviewers working independently. Studies were eligible if they reported genetic, molecular, or epigenetic data on cerebral AVMs. Because of substantial heterogeneity in designs and outcomes, evidence was synthesised qualitatively. Of 343 records, 44 primary studies (28 clinico-genetic and 16 experimental) together with 20 reviews and meta-analyses met inclusion. Inherited AVM syndromes largely reflected germline variants in the TGF-β/BMP network (ENG, ACVRL1, SMAD4, GDF2/BMP9) or in arteriovenous-specification regulators (RASA1, EPHB4); penetrance was incomplete and there was support for local modifying "second-hit" events. Resected sporadic cerebral AVMs often carried somatic activating mutations in the RAS/MAPK cascade-mostly KRAS, less often BRAF-at low variant allele fractions that demanded high-sensitivity assays. Endothelial-specific activation of KRAS or BRAF reproduced AVM-like phenotypes in vivo and showed MEK-ERK dependence. Susceptibility variants (notably at 9p21/ANRIL), inflammatory mediators, extracellular-matrix remodelling, and epigenetic changes appear to fine-tune lesion behaviour and haemorrhagic risk. Syndromic predisposition and clonal somatic events in endothelium converge on a small set of developmental signalling axes that govern angiogenesis and vessel-wall maturation. Diagnostics anchored in this biology, together with pathway-targeted therapy, now need prospective evaluation, paired with standardised approaches for detecting low-level mosaicism.
    Keywords:   KRAS ; Cerebral arteriovenous malformation; Hereditary hemorrhagic telangiectasia; MAPK signaling; Somatic mutation; Systematic review
    DOI:  https://doi.org/10.1007/s10143-026-04541-1
  11. J Cell Biol. 2026 Nov 02. pii: e202511137. [Epub ahead of print]225(11):
    ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes.
    Devin Clegg, Amanda Bentley-DeSousa, Agnes Roczniak-Ferguson, Shawn M Ferguson.
      Increased activity of leucine-rich repeat kinase 2 (LRRK2) confers Parkinson's disease risk. LRRK2 dynamically localizes to lysosomal membranes in response to various stresses, yet the mechanisms by which distinct lysosomal perturbations are communicated to LRRK2 remain unclear. Here, we show that inhibition of the lysosomal lipid kinase PIKfyve promotes LRRK2 recruitment and signaling through a pathway that requires the lysosomal chloride/proton antiporter ClC-7. ClC-7 in turn controls the accumulation of multiple Rab GTPases on lysosomes. LRRK2 signaling under these conditions requires its established Rab-binding surfaces, with Rab12 contributing significantly to this response. This pathway operates independently of CASM. In contrast, lysosomal stresses that induce CASM require both Rab-binding sites on LRRK2 and GABARAP for robust LRRK2 signaling. These findings identify ClC-7-dependent lysosomal remodeling and Rab accumulation as key features linking PIKfyve inhibition to LRRK2 signaling and reveal that distinct lysosomal stresses engage different combinations of Rab and GABARAP inputs to activate LRRK2.
    DOI:  https://doi.org/10.1083/jcb.202511137
  12. PLoS Comput Biol. 2026 Oct 21. 22(10): e1014860
    Multiscale modeling reveals non-linear dynamics of AKT-mediated NO-ROS crosstalk in shear stress-induced endothelial phenotype.
    Yu-Yuan Zhang, Yi-Teng Wang, Yan Qiu, Yong-Jiang Li, Dong Chen, Kai-Rong Qin.
      Endothelial dysfunction is a critical initiating event in atherosclerosis. The regulatory role of the AKT signaling pathway in the transition between injury and repair remains unclear. This study developed a multiscale model to elucidate how AKT signaling modulates endothelial repair under shear stress. The framework integrates hemodynamic stimuli, cellular behaviors, and nonlinear AKT/NO/ROS biochemical kinetics coupled with endothelial phenotypic transitions. Results demonstrate that endothelial dysfunction is driven by a spatial mismatch between NO production and ROS consumption rather than global deficiency. Phenotypic restoration is governed by the nonlinear interactions within the NO-ROS network. Systematic simulations identified a golden window, where Day 1 intervention and moderate AKT activation effectively restored endothelial cells and normalized redox status. Conversely, excessive activation caused supra-physiological over-suppression. These findings suggest that repair is determined by the tight coupling of redox homeostasis and immune dynamics, highlighting intervention timing and dosage as critical factors for precision vascular therapy.
    DOI:  https://doi.org/10.1371/journal.pcbi.1014860
  13. Cell Syst. 2026 Oct 20. pii: S2405-4712(26)00239-5. [Epub ahead of print] 101757
    Asymmetric crosstalk between the BMP and TGF-β pathways resolves signaling ambiguity.
    Johannes M Auth, Inbal Eizenberg-Magar, Omer Erez Dekel, Omer Zachar, Merav D Shmueli, Inbal Zigdon, Achinoam Shoham, Vladimir Mindel, Tsviya Olender, Meytar Asulin Berrebi, Ariel Tennenhouse, Neta Bar-Hai, Rakefet Ben-Yishay, Dana Ishay-Ronen, Yaron E Antebi.
      The BMP and TGF-β signaling pathways control cellular fate decisions in diverse biological contexts, often playing opposing roles. Despite extensive knowledge of these pathways, understanding how cells respond to environments containing these opposing cues remains a challenge. Here, we systematically analyze the activation of these pathways under combinatorial signaling environments. We find that TGF-β ligands inhibit BMP signaling while BMP ligands enhance TGF-β transcriptional response across concentrations, ligand variants, and cell types. This asymmetric crosstalk results in the activation of a TGF-β-biased transcriptional response even under mixed-signaling conditions, effectively reducing signal ambiguity, with implications for processes such as epithelial-to-mesenchymal transition (EMT). We show that this crosstalk originates downstream of SMAD protein phosphorylation. Using mathematical models, we predict and experimentally verify that promiscuous interactions between SMAD proteins provide the mechanism for the observed crosstalk. Our findings challenge the canonical models, suggesting an active role for mediator proteins in determining biological responses.
    Keywords:  BMP signaling; SMAD complexes; TGF-β; combinatorial signaling; mathematical modeling; signal integration; signaling; signaling crosstalk
    DOI:  https://doi.org/10.1016/j.cels.2026.101757
  14. Ageing Res Rev. 2026 Oct 17. pii: S1568-1637(26)00414-9. [Epub ahead of print]123 103422
    Tissue coordination in ageing and disease.
    Kez Cleal.
      How cellular and microenvironmental changes are translated into tissue-level decline remains incompletely understood. Here, we view tissue maintenance through the lens of multicellular coordination, defined as the endogenous management of dependencies among component activities. These dependencies are embodied in a tissue's relational state across signalling networks, epigenetic states, cell composition, and extracellular matrix. The different turnover timescales of these substrates may permit system memory and path dependence. We analyse two constraints that may limit coordination and distributed maintenance: self-reference, wherein the maintenance machinery is itself vulnerable to decline, and a sensing bottleneck, which limits the extent to which cells can perceive and represent age-related change. We explore how tissue architecture and renewal shape the consequences of these constraints for coordination, relational state and tissue function. In some cases, coordination may stabilise a pathological state even after removal of the initiating driver, creating a coordination trap. This view may help explain why tissues exhibit different age-related trajectories and suggests that interventions may also need to restore functional tissue coordination.
    Keywords:  Ageing; Biogerontology; Coordination; Coordination trap; Relational state; Systems biology; Theory of ageing; Tissue architecture
    DOI:  https://doi.org/10.1016/j.arr.2026.103422
  15. Stem Cell Reports. 2026 Oct 22. pii: S2213-6711(26)00334-6. [Epub ahead of print] 103123
    Defining early human developmental identity: A curated, cross-platform marker framework.
    Jochen Dobner, Alessandro Prigione, Andrea Rossi.
      Early human development involves dynamic cell-state transitions, complicating distinction between transient transcriptional changes and stable lineage commitment in human pluripotent stem cell models. To address this challenge, we establish a curated, cross-platform marker framework for pluripotency and early germ-layer identity. Starting from an unbiased RNA-seq discovery set, we validated candidates by qPCR and evaluated the panel across independent bulk RNA-seq and embryonic single-cell and spatial transcriptomic datasets. This yielded 67 validated markers, of which 66 were retained for downstream transcriptomic analyses. Our framework identified early developmental states across heterogeneous datasets and showed lineage-associated enrichment in human and macaque embryonic references despite substantial transcriptional variability. Protein-level concordance was observed for detectable targets in KOLF2.1J proteomic data. To enable broad application, we introduce DeepDiff, a web-based resource integrating the marker framework and enabling automated fate classification. Together, this work provides a transferable framework for assessing early developmental identity across experimental contexts.
    Keywords:  KOLF2.1J; cell identity; gastrulation; germ layer markers; human induced pluripotent stem cells; marker validation; pluripotency; trilineage differentiation
    DOI:  https://doi.org/10.1016/j.stemcr.2026.103123
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