bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2026–02–01
fourteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Transient proliferation by reversible YAP and mitogen control of the cyclin D1/p27 ratio.
  2. A new functional assay reveals that membrane binding is critical for overactivation of the phosphoinositide 3-kinase H1047R mutant.
  3. CellRank: consistent and data view agnostic fate mapping for single-cell genomics.
  4. Signaling to make human ribosomes: Connections between the cytoplasm and the nucleolus.
  5. PIK3CA Mutations Downregulate PPT1 to Promote Adipogenesis by Suppressing P300 Depalmitoylation and Phase Separation.
  6. Factors that determine cell fate in mitotically arrested cancer cells.
  7. Morphomechanic tuning of ERK by actin-TFII-IΔ regulates cell identity.
  8. Revitalizing PI3K Inhibitors for PET/CT Imaging and Radionuclide Therapy of Multiple Cancers.
  9. Nuclear phosphoinositides: An exploration into their regulation, roles and physico-chemical environment.
  10. Scalable and multiplexed recorders of gene regulation dynamics across weeks.
  11. Regulation of actin dynamics by phosphoinositides: Focus on postsynaptic plasticity.
  12. Clinical management of common toxicities with inhibitors targeting the PI3K/AKT/mTOR pathway in breast cancer.
  13. GlycoRNA complexed with heparan sulfate regulates VEGF-A signalling.
  14. Tumour endothelial cells in cancer: Chemo-physical crosstalk and angiogenic signalling in the tumour microenvironment.
  1. Commun Biol. 2026 Jan 29.
    Transient proliferation by reversible YAP and mitogen control of the cyclin D1/p27 ratio.
    Katherine R Ferrick, Samsara W Upadhya, Yilin Fan, Nalin Ratnayeke, Mary N Teruel, Tobias Meyer.
      Hippo-YAP signaling orchestrates transient proliferation during tissue repair and is therefore an attractive target in regenerative medicine. However, it is unclear how YAP integrates mitogen and contact signals to start and stop proliferation. Here we show that reduced contact inhibition, increased mitogen signaling, and YAP-TEAD activation converge on increasing the nuclear cyclin D1/p27 protein ratio during early G1 phase, towards a threshold ratio that dictates whether individual cells enter or exit the cell cycle. YAP increases this ratio in concert with inducing mitogen signaling, by increasing EGFR and other receptors that signal primarily through ERK. After a delay, contact inhibition suppresses YAP activity, which gradually downregulates mitogen signaling and the cyclin D1/p27 ratio. Thus, critical for regeneration without cancer initiation, robust proliferation responses result from a YAP-induced and receptor-mediated prolonged increase in the cyclin D1/p27 ratio, which is reversed by delayed suppression of receptor signaling after contact inhibition of YAP.
    DOI:  https://doi.org/10.1038/s42003-026-09590-2
  2. J Biol Chem. 2026 Jan 23. pii: S0021-9258(26)00077-3. [Epub ahead of print] 111207
    A new functional assay reveals that membrane binding is critical for overactivation of the phosphoinositide 3-kinase H1047R mutant.
    Alexandra Papafotika, Maria Pavlaki, Vasiliki Lazani, Vasiliki Elpida Karamani, Dimitris Aggelidis, Anna Kapella, Danai Maria Kotzampasi, Bogos Agianian, Argiris Efstratiadis, Zoe Cournia, Savvas Christoforidis.
      PIK3CA encodes the catalytic subunit of class I PI3Kα (p110α), a key enzyme in receptor-mediated signaling that phosphorylates phosphatidylinositol-4,5-bisphosphate to the 3,4,5-triphosphate lipid. This gene is frequently mutated in cancers, with H1047R and E545K being the most prevalent mutations. However, the mechanisms of mutants' overactivation remain incompletely understood. Here, we report the development of a PI3Kα activity assay using reconstituted liposomes, which we employed to address the role of lipid membranes on mutant overactivation. The assay was validated by assessing typical enzymatic features and by confirming the IC50 of well-known inhibitors and the activation by a phosphopeptide mimicking receptor-mediated stimulation. Additionally, we examined the impact of lipid membranes on mutant overactivation by comparing WT and mutant activities with soluble or liposomal PIP2. Interestingly, we discover that the membrane form of the substrate is crucial for the catalytic overactivation of H1047R, whereas E545K overactivation occurs independently of membranes. Consistently, molecular dynamics simulations of ΔABD p110α on a model membrane, performed for WT and H1047R, revealed structural and dynamic changes induced by H1047R, including stabilization of the C-terminal tail on the membrane and altered dynamics of membrane-binding loop 2 residues, suggesting enhanced membrane binding. Intriguingly, in agreement with the above findings, surface plasmon resonance assays reveal higher rate of association of H1047R-PI3Kα with the membrane. Altogether, our data suggest that the overactivation of the H1047R mutant is due to increased rate of membrane binding, providing novel mechanistic insights into how this hot spot mutation leads to catalytic overactivation and contributes to oncogenesis.
    Keywords:  MD simulations; PI3Kinase; assay development; cancer; enzymatic activity; enzyme mutation; lipid-protein interactions; liposome; mutant overactivation; oncogene
    DOI:  https://doi.org/10.1016/j.jbc.2026.111207
  3. Nat Protoc. 2026 Jan 29.
    CellRank: consistent and data view agnostic fate mapping for single-cell genomics.
    Philipp Weiler, Fabian J Theis.
      Single-cell RNA sequencing quantifies biological samples at an unprecedented scale, allowing us to decipher biological differentiation dynamics such as normal development or disease progression. As conventional single-cell RNA sequencing experiments are destructive by nature, reconstructing cellular trajectories computationally is an essential aspect of analysis pipelines. To infer trajectories in a consistent and scalable manner, we have developed CellRank. In its first iteration, CellRank quantitatively recovered trajectories from RNA velocity estimates and transcriptomic similarity. Given these data views, CellRank constructed a cell-cell transition matrix, inducing a Markov chain to automatically infer terminal states and describe their lineage formation. However, CellRank did not enable incorporating complementary data views such as experimental time points, pseudotime or stemness potential. To facilitate these and future views, CellRank 2 generalizes CellRank's trajectory inference framework to multiview single-cell data, leading to a general and scalable framework for cellular fate mapping. Overall, the CellRank framework enables the consistent quantification of cellular fate, combining complementary views and analyzing lineage priming consistently. Here we provide detailed protocols on how to run exemplary CellRank analyses at scale and across different data views. Using CellRank requires basic apprehension and knowledge of single-cell omics data and the Python programming language.
    DOI:  https://doi.org/10.1038/s41596-025-01314-w
  4. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00027-4. [Epub ahead of print]
    Signaling to make human ribosomes: Connections between the cytoplasm and the nucleolus.
    Isabella R Lawrence, Emily C Sutton, Shivang Bhaskar, Susan J Baserga.
      Ribosome biogenesis is a complex, multi-step cellular process that begins in the nucleolus and produces ribosomes that translate mRNA into proteins in the cytoplasm. This process is essential for cellular growth yet is resource intensive. It is therefore tightly coordinated with cytoplasmic requirements, energy availability, and the cell cycle through several kinase signaling pathways. Increasing evidence indicates that proteins shared between the cytoplasm and nucleolus may enhance this coordination. Here, we evaluate the interplay between the cytoplasm and nucleolus in human cells, presenting an intricate bidirectional regulatory network with emerging clinical relevance. We describe the phosphorylation events that promote ribosome biogenesis during interphase, focusing on mammalian target of rapamycin complex 1 (mTORC1), extracellular signal-regulated kinase (ERK), and casein kinase II (CK2). By contrast, protein phosphorylation inactivates ribosome biogenesis during mitosis. We further summarize several factors shared among the mitotic machinery, cytoplasmic organelles, and the nucleolus. Moreover, we highlight the mounting evidence that dysregulated cytoplasmic-nucleolar feedback contributes to the progression of several diseases.
    Keywords:  cancer; endoplasmic reticulum; lysosome; mTOR; mitochondria; mitosis; muscle atrophy; rRNA; ribosome biogenesis; ribosomopathies
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.007
  5. Adv Sci (Weinh). 2026 Jan 29. e23139
    PIK3CA Mutations Downregulate PPT1 to Promote Adipogenesis by Suppressing P300 Depalmitoylation and Phase Separation.
    Hongrui Chen, Zening Huang, Rui Chang, Wei Gao, Yajing Qiu, Bin Sun, Chen Hua, Xiaoxi Lin.
      PIK3CA mutations drive benign adipose overgrowth in facial infiltrating lipomatosis (FIL), but the downstream molecular mechanisms remain incompletely understood. This study investigated the role of palmitoyl-protein thioesterase 1 (PPT1)-mediated depalmitoylation in regulating aberrant adipogenesis induced by mutant PIK3CA. Using single-cell RNA-seq, molecular dynamics simulations, and functional assays in primary human FIL adipose-derived stem and progenitor cells (ASPCs), immortalized cell lines, and mouse models, we dissected the signaling pathway linking PIK3CA mutation to adipogenesis. Techniques included ChIP-qPCR, acyl-biotin exchange assays, luciferase reporter assays, and RNA/ATAC sequencing. PIK3CA mutations transcriptionally repressed PPT1 via PI3K-AKT-c-JUN signaling. Downregulated PPT1 enhanced palmitoylation of the transcriptional coactivator P300 at C1176. This modification stabilized P300 by impairing its interaction with HSC70 and subsequent chaperone-mediated lysosomal degradation. Furthermore, C1176 palmitoylation inhibited P300 phase separation, thereby preserving its histone acetyltransferase activity. Sustained P300 activity promoted chromatin accessibility and expression of adipogenic genes, driving excessive adipogenesis in FIL. These findings established a novel "palmitoylation-phase separation-epigenetic regulation" axis in cellular fate determination and revealed PPT1 and P300 as potential therapeutic targets for FIL.
    Keywords:  PIK3CA; adipogenesis; palmitoylation; phase separation
    DOI:  https://doi.org/10.1002/advs.202523139
  6. Front Cell Dev Biol. 2025 ;13 1691574
    Factors that determine cell fate in mitotically arrested cancer cells.
    Naghmana Ashraf, Roaa Kassim, Edward Goldstein, Taylor Landfair, Clarissa G Nuñez, Jeffrey B Arterburn, Charles B Shuster.
       Introduction: Cancer cells display a high degree of heterogeneity in their responses to mitotic arrest, from apoptosis during mitosis to surviving mitotic failure and continuing to progress through the cell cycle. Thus, understanding the basis for this variation may prove valuable for developing more effective chemotherapeutic strategies.
    Methods: A combination of biochemical and long-term live cell imaging approaches were applied to determine whether inhibition of Phosphoinositide 3-kinase (PI3K) signaling affected apoptosis in cancer cells arrested in prometaphase with a Kinesin Spindle Protein (KSP) inhibitor.
    Results: Dual inhibition of KSP and PI3K signaling induced apoptosis more effectively than mitotic arrest or PI3K pathway inhibition alone. Live cell imaging with probes for mitotic progression and apoptosis revealed that HeLa cells that died during mitotic slippage underwent apoptosis during prometaphase arrest, suggesting that PI3K inhibition dramatically shifted the dynamics of cell death. Similar potentiation of mitotic cell death could be detected in SiHa cells, whereas other cancer or non-transformed cell lines were not sensitized by PI3K inhibition. Expression of constitutively active Rap1, which modulates both cell adhesion and PI3K activity, significantly increased the duration of mitotic arrest in a PI3K-dependent manner. Moreover, activated Rap1 significantly increased the fraction of cells that slipped completely back into interphase prior to apoptotic cell death.
    Conclusions: These results shed insights into possible mechanisms by which cells may evade cell death during mitotic delay and suggest a strategy to optimize antimitotic interventions.
    Keywords:  Rap1; apoptosis; kinesin spindle protein; mitosis; mitotic slippage; phosphoinositide-3-kinase
    DOI:  https://doi.org/10.3389/fcell.2025.1691574
  7. bioRxiv. 2024 Oct 01. pii: 2023.06.02.543427. [Epub ahead of print]
    Morphomechanic tuning of ERK by actin-TFII-IΔ regulates cell identity.
    Qiao Wu, Jian Zhang, Bing Long, Xiao Hu, Bruna Mafra de Faria, Stephen Maxwell Scalf, Kutay Karatepe, Wenxiang Cao, Nikolaos Tsopoulidis, Andres Binkercosen, Masaki Yagi, Aaron Weiner, Mary Kaileh, Enrique M De La Cruz, Ananda L Roy, Konrad Hochedlinger, Shangqin Guo.
      Cell morphology is faithfully coupled to its identity but the coupling mechanism remains elusive. Using somatic cell reprogramming into pluripotency as a model system, we show that activity of the extracellular signal-regulated kinase (ERK) is tuned by cellular morphomechanic state to direct cell fate. Pluripotent cells and somatic cells reprogramming into pluripotency allocate large amounts of actin into their nucleus, which morphs cells to become taller than 10 μm, a minimal height required for the pluripotent identity. Accumulated nuclear actin binds to TFII-IΔ, an atypical transcription factor that translocates into the nucleus upon signaling. TFII-IΔ also binds to and activates ERK. The binding of TFII-IΔ by nuclear actin reduces ERK activity, in coordination with changes in cell/colony height. The tight coupling between cell height and nuclear actin accumulation necessitates the degree of ERK tuning to be mild. Mild ERK inhibition by chemicals recapitulates the tuning by actin-TFII-IΔ and turns most cells in reprogramming cultures into pluripotency. Thus, we uncover a novel mechanism for how cell morphology couples to its identity via the actin-TFII-IΔ-ERK axis, identifying points of intervention in cell fate manipulation.
    DOI:  https://doi.org/10.1101/2023.06.02.543427
  8. J Med Chem. 2026 Jan 27.
    Revitalizing PI3K Inhibitors for PET/CT Imaging and Radionuclide Therapy of Multiple Cancers.
    Hongyi Huang, Shouguo Peng, Quan Zuo, Siqi Zhang, Jiang Wu, Yumeng Zhang, Xueyao Chen, Qingshuang Lu, Qichen Hu, Shuo Jiang, Jieting Shen, Jie Yan, Jiaqi Hu, Junlong Lu, Feng Wang, Rui Wang, Heng Xu, Kuan Hu.
      Phosphoinositide 3-kinase (PI3K) dysregulation drives tumorigenesis through regulation of cell cycle progression and survival. Several small molecular inhibitors targeting PI3K have been approved for tumor treatment. However, these inhibitors exposed unexpected severe off-tumor toxicity, leading to poor patient prognosis. Radiopharmaceuticals based on radiolabeled PI3K inhibitors for targeted internal radionuclide therapy offer a revitalized therapeutic approach to reduced pharmacological toxicity. Herein, we rationally designed and synthesized four bifunctional radiolabeled small-molecule chimeras based on the PI3K inhibitor IMM-H012, denoted as [68Ga]Ga/[177Lu]Lu-P(1-4). Among them, radiolabeled P4 demonstrated superior pharmacodynamic and pharmacokinetic profiles in multiple tumor models. Moreover, [177Lu]Lu-P4 substantially suppressed subcutaneous melanoma tumor growth with an acceptable safety profile. Additionally, [177Lu]Lu-P4 combined with IMM-H012 showed synergistic antitumor effects. The mechanistic study suggested a novel radiosensitization mechanism of 177Lu to PI3K inhibitors by downregulating fatty acid oxidase expression. These findings reposition PI3K as a versatile theranostic target while providing an effective repurposing strategy for PI3K inhibitors.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c03583
  9. Biochim Biophys Acta Mol Cell Biol Lipids. 2026 Jan 22. pii: S1388-1981(26)00011-9. [Epub ahead of print]1871(3): 159725
    Nuclear phosphoinositides: An exploration into their regulation, roles and physico-chemical environment.
    Charlotte L Collier, Palita Udomjarumanee, Lee Morgan, Joaquin Cardenas Rodriguez, Muhammad Bilal Qasim, Bhavwanti Sheth, Imogen Taylor, Sonakshi Gehlot, Stefano Leto, Roberta Fiume, Nullin Divecha.
      Polyphosphoinositides are phospholipids consisting of a diacylglycerol backbone linked to an inositol headgroup that can be phosphorylated at three positions, generating seven distinct lipid species. Their levels are tightly regulated by coordinated kinase, phosphatase, and phospholipase activities, each responsive to diverse cellular cues. The functional diversity of phosphoinositides arises from their ability to bind specific protein domains, thereby influencing protein localisation, activity, and interaction networks. Although traditionally associated with membrane-bound compartments, phosphoinositides are also present within the nucleus, not only at the nuclear envelope but also within a variety of membrane-less nuclear structures. The identification of nuclear phosphoinositide-binding proteins has revealed that phosphoinositides contribute to the regulation of multiple nuclear processes, including transcription, RNA maturation and export, DNA damage responses, and broader nuclear stress signalling. In this review, we summarise the mechanisms by which nuclear phosphoinositides are generated, spatially organised, and interpreted by downstream effectors, and we highlight key outstanding questions that remain to be resolved.
    Keywords:  Epigenetic signalling; Histone modification; Lipid kinases; Nuclear phosphoinositides; Phase separated nuclear compartments; Phosphoinositide signalling; Phospholipase C; RNA splicing
    DOI:  https://doi.org/10.1016/j.bbalip.2026.159725
  10. Nature. 2026 Jan 26.
    Scalable and multiplexed recorders of gene regulation dynamics across weeks.
    Lirong Zheng, Dongqing Shi, Yixiao Yan, Bingxin Zhou, Jormay Lim, Yongjie Hou, Bobae An, Jason K Adhinarta, Michael Lin, BumJin Ko, William C Joesten, Mehul Gautam, Elie D M Huez, Eung Chang Kim, Emily G Klyder, Boxuan Chang, Sethuramasundaram Pitchiaya, Michael T Roberts, Denise J Cai, Edward S Boyden, Donglai Wei, Pietro Liò, Changyang Linghu.
      Gene expression is dynamically regulated by gene regulatory networks comprising multiple regulatory components to mediate cellular functions1. An ideal tool for analyzing these processes would track multiple-component dynamics with both spatiotemporal resolution and scalability within the same cells, a capability not yet achieved. Here, we present CytoTape, a genetically encoded, modular protein tape recorder for multiplexed and spatiotemporally scalable recording of gene regulation dynamics continuously for up to three weeks, physiologically compatible, with single-cell, minutes-scale resolution. CytoTape employs a flexible, thread-like, elongating intracellular protein self-assembly engineered via computationally assisted rational design, built on earlier XRI technology2. We demonstrated its utility across multiple mammalian cell types, achieving simultaneous recording of five transcription factor activities and gene transcriptional activities. CytoTape reveals that divergent transcriptional trajectories correlate with transcriptional history and signal integration, and that distinct immediate early genes (IEGs) exhibit complex temporal correlations within single cells. We further extended CytoTape into CytoTape-vivo for scalable, spatiotemporally resolved single-cell recording in the living brain, enabling simultaneous weeks-long recording of doxycycline- and IEG promoter-dependent gene expression histories across up to 14,123 neurons spanning multiple brain regions per mouse. Together, the CytoTape toolkit establishes a versatile platform for scalable and multiplexed analysis of cell physiological processes in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s41586-026-10156-9
  11. Biochim Biophys Acta Mol Cell Biol Lipids. 2026 Jan 22. pii: S1388-1981(26)00012-0. [Epub ahead of print] 159726
    Regulation of actin dynamics by phosphoinositides: Focus on postsynaptic plasticity.
    Joseph P Albanesi, Jen Liou, Jui-Yu Yeh, Helen L Yin.
      Phosphoinositides, most prominently phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate, regulate the activities of a wide range of proteins that control the polymerization, depolymerization, and branching of actin filaments. This phosphoinositide-mediated remodeling of the actin cytoskeleton is crucial for a many cellular functions, including migration, division, and intracellular organelle transport. As a unifying theme in this review, we have chosen to focus on the role of phosphoinositides in regulating actin dynamics during dendritic spine plasticity. As in other biological systems, actin polymerization and branching drive morphological changes in dendritic spines by exerting force on the plasma membrane, creating structures such as filopodial protrusions and bulbous spine heads. Activity-dependent changes in the number, size, and shape of dendritic spines underlie fundamental brain functions such as learning and memory and are often disrupted in cognitive and neurological disorders. Hence, the control of actin regulatory proteins in dendritic spines by phosphoinositides has been, and remains, an extremely active area of investigation.
    Keywords:  Actin branching; Actin polymerization; Dendritic spines; Phosphoinositides; Synaptic plasticity
    DOI:  https://doi.org/10.1016/j.bbalip.2026.159726
  12. ESMO Open. 2026 Jan 27. pii: S2059-7029(25)01806-X. [Epub ahead of print]11(2): 105936
    Clinical management of common toxicities with inhibitors targeting the PI3K/AKT/mTOR pathway in breast cancer.
    K L Jhaveri, N M Iyengar, N C Turner, H S Rugo, J O'Shaughnessy, C H Barrios, G Curigliano, F André, S-A Im, M D Goncalves, M E Lacouture, P A Fasching, R Leung.
      Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been implicated in oncogenesis, treatment resistance, and disease progression, making it an attractive target for anticancer drug development. Early experiences with PI3K/AKT/mTOR inhibitors have highlighted challenges associated with their modest efficacy, as well as safety and tolerability issues; however, several effective next-generation PI3K/AKT/mTOR inhibitors have now been approved for patients with breast cancer. As a result, there is a growing need to understand the presentation, characteristics, and management of common toxicities (hyperglycemia, rash, stomatitis, and diarrhea). This review summarizes available safety data from phase III randomized clinical trials for approved PI3K/AKT/mTOR pathway-targeted therapies (everolimus, alpelisib, capivasertib, and inavolisib), including incidence, severity, adverse event-related dose modifications, and time to onset. We also provide guidance for preparation, monitoring, and management strategies for integrating these therapies into clinical practice, with the hope that appropriate support will allow patients to tolerate higher PI3K/AKT/mTOR inhibitor dose intensities, which has the potential to translate to improved patient outcomes.
    Keywords:  PI3K/AKT/mTOR inhibitors; diarrhea; hyperglycemia; rash; stomatitis
    DOI:  https://doi.org/10.1016/j.esmoop.2025.105936
  13. Nature. 2026 Jan 28.
    GlycoRNA complexed with heparan sulfate regulates VEGF-A signalling.
    Peiyuan Chai, Sina Kheiri, Andrew Kuo, Jessica Shah, Lauren Kageler, Ruiqi Ge, Jonathan Perr, Jennifer Porat, Charlotta G Lebedenko, Joao M L Dias, Eliza Yankova, Sandeep K Rai, Christopher P Watkins, Petar Hristov, Konstantinos Tzelepis, Timothy Hla, Ritu Raman, Eliezer Calo, Jeffrey D Esko, Ryan A Flynn.
      Heparan sulfate proteoglycans (HSPGs) have been recognized as key plasma membrane-tethered co-receptors for a broad range of growth factors and cytokines containing cationic heparan-binding domains1,2. However, how HSPGs mechanistically mediate signalling at the cell surface-particularly in the context of cell surface RNA-remain poorly understood. During developmental and disease processes, vascular endothelial growth factor (VEGF-A), a heparan sulfate-binding factor, regulates endothelial cell growth and angiogenesis3. The regulatory paradigm for endothelial cell-mediated selectively of VEGF-A binding and activity has largely been focused on understanding the selective sulfation of the anionic heparan sulfate chains4-8. Here we examine the organizational rules of a new class of anionic cell surface conjugates, glycoRNAs9,10, and cell surface RNA-binding proteins (csRBPs11,12). Leveraging genome-scale knockout screens, we discovered that heparan sulfate biosynthesis and specifically the 6-O-sulfated forms of heparan sulfate chains are critical for the assembly of clusters of glycoRNAs and csRBPs (cell surface ribonucleoproteins (csRNPs)). Mechanistically, we show that these clusters antagonize heparan sulfate-mediated activation of ERK signalling downstream of VEGF-A. We demonstrate that the heparan sulfate-binding domain of VEGF-A165 is responsible for binding RNA, and that disrupting this interaction enhances ERK signalling and impairs vascular development both in vitro and in vivo and is conserved across species. Our study thus uncovers a previously unrecognized regulatory axis by which csRNPs negatively modulate heparan sulfate-mediated signalling in the context of angiogenesis driven by VEGF-A.
    DOI:  https://doi.org/10.1038/s41586-025-10052-8
  14. Cell Signal. 2026 Jan 23. pii: S0898-6568(26)00041-0. [Epub ahead of print]141 112391
    Tumour endothelial cells in cancer: Chemo-physical crosstalk and angiogenic signalling in the tumour microenvironment.
    Arian Ansardamavandi, Mohammad Tafazzoli-Shadpour.
      The tumour microenvironment (TME) represents a complex, dynamic ecosystem comprising cellular and acellular elements that collectively facilitate tumour progression, invasion, and metastasis through intricate chemo-mechanical interactions. Cancer cells drive TME remodelling by recruiting and reprogramming stromal components, including cancer-associated fibroblasts (CAFs) that alter extracellular matrix (ECM) composition and stiffness, tumour-associated macrophages (TAMs) that promote immunosuppressive conditions, and tumour endothelial cells (TECs) that establish aberrant vascular networks. This review synthesises current literature on the pivotal role of TECs in tumour angiogenesis, emphasising their bidirectional crosstalk with cancer and stromal cells via chemical signals (e.g., growth factors under hypoxia) and mechanical cues (e.g., ECM stiffness and topography) that modulate cellular contractility, adhesion, and biochemical release. Key findings reveal how TECs integrate these multifaceted stimuli to orchestrate vascular remodelling, enhance permeability, and foster metastatic dissemination, often through dysregulated pathways distinct from normal endothelium. Ultimately, elucidating these mechanisms offers promising avenues for developing targeted therapies that selectively inhibit TEC-mediated angiogenesis while preserving physiological vascular function.
    Keywords:  Angiogenesis; Cancer; Cellular cross-talk; Chemical and mechanical stimuli; Tumour endothelial cells; Tumour microenvironment
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112391
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