bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2026–08–16
eleven papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Oncogenic PIK3CA enhances collective migration of mammary epithelial cells through ERK wave propagation.
  2. Insulin receptor substrate 2 (IRS2) confers resistance to PI3K pathway inhibition in PIK3CA mutant breast cancer.
  3. Acute AKT signaling increases glucose phosphorylation and contribution to glycogen in hepatocytes.
  4. Suppression of EGFR signaling and drug-induced potentiation are widespread features of oncogenic RTK fusions.
  5. Targeting KIT prevents brain arteriovenous malformations driven by ALK1-deficient angiogenic endothelial cells.
  6. A quantitative model of a phenotypically variable genetic defect.
  7. mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency.
  8. Mechanistic machine learning for prediction of prime editing outcomes.
  9. Human iPSC-derived vascularized organoids: Strategy-based insights from 2D endothelial cells to 3D blood vessel organoids.
  10. Systematic differences in protein stability underlie species-specific developmental tempo.
  11. Proteasome-dependent protein degradation shapes developmental tempo in mouse and human neural progenitors.
  1. J Cell Sci. 2026 Aug 01. pii: jcs264916. [Epub ahead of print]139(15):
    Oncogenic PIK3CA enhances collective migration of mammary epithelial cells through ERK wave propagation.
    Ali Dayoub, Artem I Fokin, Sergey Leonov, Alexis M Gautreau, Antonina Y Alexandrova.
      Oncogenic mutations of the PIK3CA gene, which encodes the catalytic subunit of the phosphatidylinositol 3-kinase (PI3K) enhance cell migration via ERK (ERK1 and ERK2, also known as MAPK3 and MAPK1, respectively) activation. We analyzed the factors regulating collective cell migration (CCM) of genome-edited MCF10A cell lines carrying hotspot PIK3CA mutations E545K or H1047R. H1047R enhanced CCM and promoted the propagation of waves of ERK activity backwards from the wound edge, whereas E545K impaired both coordinated CCM and ERK activity wave formation. The distance traveled by ERK activity waves correlated with directional persistence of migrating cells. Inhibition of cell contractility stimulated ERK wave propagation and efficient CCM of E545K cells but impaired ERK waves and CCM in control cells. Impaired ERK wave propagation was consistently associated with non-linear cell-cell junctions and the loss of polarized distribution of actomyosin. Taken together, these analyses suggest that polarized actomyosin contractility and pulsatile ERK activation must be constrained in the territory of a phase diagram compatible with mechanotransduction of ERK waves across cell-cell junctions to achieve highly coordinated and efficient collective migration.
    Keywords:  Cell contractility; ERK waves; Oncogenic mutation; PIK3CA; Wound healing
    DOI:  https://doi.org/10.1242/jcs.264916
  2. J Biol Chem. 2026 Aug 10. pii: S0021-9258(26)02298-2. [Epub ahead of print] 113426
    Insulin receptor substrate 2 (IRS2) confers resistance to PI3K pathway inhibition in PIK3CA mutant breast cancer.
    Michael W Lero, Jennifer S Morgan, Michael-Anthony Card, Lihua Julie Zhu, Junhui Li, Rui Li, Quyen Thu Bui, Emma Mohlmann, Hira L Goel, Leslie M Shaw.
      Activating mutations in PI3K are one of the most frequent mutations in breast cancer and are associated with worse patient outcomes in many breast cancer subtypes. Despite intense interest, cancer treatments that target the PI3K pathway have been only modestly effective due to intrinsic and acquired resistance mechanisms which reactivate PI3K signaling. Here, we characterize a feedback mechanism by which PI3K pathway inhibitors increase insulin receptor substrate 2 (IRS2) abundance and demonstrate the role of IRS2 in promoting resistance to these drugs. In PIK3CA mutant breast tumors and cell lines, there is a significant reduction in IRS2 mRNA and protein abundance which is reversed by PI3K pathway inhibition and mediated by the transcription factors FOXO1 and FOXO3. PIK3CA mutations do not alter IRS1 expression. IRS2 confers resistance to PI3K pathway inhibition by sustaining PI3K signaling in PIK3CA mutant, but not wild-type breast cancer cells. Increased IRS2 abundance also correlates with PI3K pathway inhibitor resistance across PIK3CA mutant cancer cell lines from a variety of tissues. The clinical relevance of these findings is highlighted by the frequency of PI3K mutations in cancer and the identification of a new target to address the challenges associated with prior efforts to block the reactivation of PI3K signaling during PI3K inhibition.
    Keywords:  AKT; Breast Cancer; Cell Death; Cell Proliferation; Cell Viability; IRS2; Insulin receptor substrate 1 (IRS1); PI3K; PIK3CA
    DOI:  https://doi.org/10.1016/j.jbc.2026.113426
  3. iScience. 2026 Aug 21. 29(8): 116956
    Acute AKT signaling increases glucose phosphorylation and contribution to glycogen in hepatocytes.
    Megan Stefkovich, Won Dong Lee, Talia Coopersmith, Joseph A Baur, Joshua D Rabinowitz, Paul M Titchenell.
      Insulin's regulation of hepatic glucose production and glycogen is critical for postprandial glucose disposal. AKT, a serine-threonine kinase and insulin signaling intermediate, regulates liver glucose metabolism through transcriptional and posttranslational mechanisms. However, current knowledge largely stems from genetic loss-of-function models, precluding observation of AKT's non-transcriptional effects. To measure rapid changes to glucose and glycogen metabolism, isotope tracing using [U-13C]-glucose and [U-14C]-glucose was coupled with the AKT inhibitor MK-2206 in primary rat hepatocytes. MK-2206 treatment decreased AKT phosphorylation and glucose contribution to glucose 6-phosphate and uridine diphosphate glucose within minutes without affecting metabolite pool sizes or protein levels of glucokinase, glucose 6-phosphatase, or phosphoenolpyruvate carboxykinase. MK-2206 also decreased glucose contribution to glycogen, independent of glycogen breakdown or glycogen synthase phosphorylation. These results demonstrate that AKT acutely regulates glucose contribution to glycogen and upstream precursors, suggesting a transcription-independent mechanism that is proximal to glucose 6-phosphate generation for glycogen synthesis.
    Keywords:  glucokinase; gluconeogenesis; glucose 6-phosphate; glucose homeostasis; glycogen; glycolysis
    DOI:  https://doi.org/10.1016/j.isci.2026.116956
  4. Proc Natl Acad Sci U S A. 2026 08 18. 123(33): e2529373123
    Suppression of EGFR signaling and drug-induced potentiation are widespread features of oncogenic RTK fusions.
    Yuzhi Carol Gao, David Gonzalez-Martinez, Sofia Wissert, Hana Bader, Nidhi Sahni, Anh Le, Robert C Doebele, Lukasz J Bugaj.
      Regulation of cancer cells by their environment contributes to tumorigenesis and drug response, though the extent to which the oncogenic state can alter a cell's perception of its environment is not clear. EML4-ALK is a receptor tyrosine kinase (RTK) fusion oncoprotein that suppresses transmembrane EGFR signaling in cancer cells. ALK inhibition restores signaling through EGFR, thereby promoting survival and drug tolerance. Here, we tested whether such modulation of EGFR activity was common among other RTK fusions, which collectively are found in ~5% of all cancers. Using live- and fixed-cell microscopy in isogenic and patient-derived cell lines, we found that a wide variety of RTK fusions suppress transmembrane EGFR, through mechanisms that include the sequestration of the adaptor protein Grb2. Targeted therapies rapidly released Grb2 from sequestration and potentiated EGFR. Synthetic optogenetic analogs of RTK fusions confirmed that cytoplasmic sequestration of Grb2 was sufficient to suppress perception of extracellular EGF and could do so without driving signaling from the synthetic fusion itself, demonstrating that fusion signaling and suppression of EGFR signaling could be functionally decoupled. Our study uncovers that a large number of RTK fusions simultaneously act as both activators and suppressors of signaling, the mechanisms of which could be exploited for biomimetic therapies that enhance cell killing and suppress drug tolerance.
    Keywords:  RTK fusions; adapters; cancer signaling; optogenetics; targeted therapies
    DOI:  https://doi.org/10.1073/pnas.2529373123
  5. J Clin Invest. 2026 Aug 11. pii: e197587. [Epub ahead of print]
    Targeting KIT prevents brain arteriovenous malformations driven by ALK1-deficient angiogenic endothelial cells.
    Elise Drapé, Lauranne Carrier, Gael Cagnone, Atik Rm Fuad, Mathilde Bizou, Damian A Sanchez, Typhaine Anquetil, Jack Wang, Halima Drissi Touzani Walali, Adnan Gopinadhan, Patrick Piet van Vliet, Joel P Howard, Mysha Ibnat, Gregor Andelfinger, Ethan Winkler, Bruno Larrivée, Alexandre Dubrac.
      Hereditary Hemorrhagic Telangiectasia type 2 (HHT2), caused by mutations in ACVRL1 ( also known as ALK1), is characterized by brain arteriovenous malformations (bAVMs), abnormal artery-vein connections for which treatment options remain limited. Despite evidence of endothelial cell (EC) heterogeneity, its role in bAVM pathogenesis remains poorly defined. Using endothelial-specific inducible Alk1 knockout mice (Alk1iECKO) and regionally resolved single-cell RNA sequencing, we show that loss of ALK1 signaling induces bAVMs predominantly in the perineural vascular plexus (PNVP). This process is driven by the emergence of a KIT+ angiogenic EC population with human AVM-like transcriptional features, including tip-cell markers and activation of PI3K and KRAS signaling pathways. Cross-species analyses and validation in human samples demonstrate that KIT expression is conserved in endothelial cells from both sporadic and HHT2 brain AVMs. Drug repurposing analysis identified KIT as a top actionable target, and we show that Kit is directly repressed by BMP9-ALK1-SMAD4 signaling. Pharmacological inhibition of KIT reduced angiogenic reprogramming and vascular malformations in vivo without affecting normal vasculature. These findings identify a pathogenic angiogenic EC state and position KIT signaling as a therapeutically actionable pathway in brain AVMs.
    Keywords:  Angiogenesis; Cell biology; Endothelial cells; Transcriptomics; Vascular biology
    DOI:  https://doi.org/10.1172/JCI197587
  6. Proc Natl Acad Sci U S A. 2026 Aug 18. 123(33): e2619147123
    A quantitative model of a phenotypically variable genetic defect.
    Alison G Simpkins, Dominic J Skinner, Brox Felix, Robert A Marmion, Jodi Schottenfeld-Roames, Stanislav Y Shvartsman.
      Phenotypic variability is a hallmark of human disease. It results from a combination of genetic modifiers, environment, and stochastic effects, but their contributions are hard to disentangle. Here, we establish the specification of terminal cells in the Drosophila tracheal system as a model for phenotypic variability and phenotypic emergence in Mendelian disorders. By perturbing Fibroblast growth factor (FGF) ligand dosage, which leads to a loss of terminal cells, we find that both microenvironmental and stochastic effects contribute to variability in terminal cell specification. We demonstrate that the phenotype results from reduced Ras-ERK signaling and use live imaging to identify molecular and morphological features of successful and failed terminal cell specification. Finally, using liability-threshold modeling, we quantify the relative magnitudes of genetic perturbations, microenvironmental effects, and stochasticity, establishing a strategy for dissecting the origins of phenotypic variability.
    Keywords:  Drosophila trachea; FGF signaling; phenotypic variability
    DOI:  https://doi.org/10.1073/pnas.2619147123
  7. Genes Dev. 2026 Aug 10.
    mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency.
    Wenjun Fan, Hester Liu, Liling Yang, Niladri Sinha, Marco Catipovic, Daoyuan Dong, Hariharan Easawaran, Rachel Green, Marikki Laiho.
      Ribosome biogenesis is a resource-consuming process that facilitates rapid growth and feeds uncontrolled, cancerous traits. Constraining ribosome biogenesis and protein translation has become a tenable therapeutic strategy for cancer. Yet, we do not know how cells that rely on high metabolic activity adapt and sustain their growth when deprived of their translational capacity. Conversely, stem cells and treatment-resistant cells persist under low metabolic states challenging their eradication. These are critical questions in cancer therapies. To delineate survival mechanisms that allow cancer cells to adapt to ribosome biogenesis defects, we conducted functional genomics screens during inhibition of RNA polymerase I. We identified that inactivation of mTOR enabled cell survival despite severe translational suppression. This was paradoxical as activation of mTOR is considered oncogenic by boosting ribosome biogenesis and cellular translational programs. We show that mTORC1 inhibition does neither restore rRNA synthesis nor ribosome biogenesis, but redistributes limited ribosomes from highly translated 5'TOP mRNAs to survival-essential transcripts. This mTOR inactivation-mediated prioritization of translational resources represents a minimal requirement for cell survival when translational capacity is compromised, which we term "translational fitness." Our findings redefine the role of mTOR in cell survival and highlight the need for strategic targeting of translation regulation in cancer therapy.
    Keywords:  adaptive survival; cancer cell survival; mTORC1 signaling; ribosome biogenesis; therapy resistance; translational control; translational fitness
    DOI:  https://doi.org/10.1101/gad.353708.126
  8. Nat Biotechnol. 2026 Aug 12.
    Mechanistic machine learning for prediction of prime editing outcomes.
    Alvin Hsu, Peter J Chen, Angus H Li, Colin F Hemez, Xin D Gao, Markus Terrey, Charlie Nelson, Vijay Selvam, Ana Cristian, Amber N McElroy, Benjamin J Steinbeck, Gandhar K Mahadeshwar, Smriti Pandey, Zachary Barsdale, Paul Z Chen, Alexander A Sousa, Holt A Sakai, Rachel A Silverstein, Ilias Morad, Ryan K Krueger, Max W Shen, Benjamin P Kleinstiver, Cathleen M Lutz, Jakub Tolar, Bruce R Blazar, Mark J Osborn, David R Liu.
      Prime editing (PE) can make specific local changes to genomic DNA in living systems but its efficient application currently requires extensive optimization of PE guide RNA (pegRNA) sequences. Here we present OptiPrime, a machine learning model of PE efficiency based on current understanding of PE mechanisms. OptiPrime achieves state-of-the-art accuracy on PE efficiency prediction and enables prediction of nicking guide RNA (PE3) and dual pegRNA (twinPE) outcomes. We validate that OptiPrime has learned the determinants of mammalian mismatch repair (MMR) and is well suited for nominating MMR-evasive silent edits that improve PE efficiency. We demonstrate the use of OptiPrime in a variety of prospective therapeutic contexts in primary human and mouse cells. Lastly, we show that OptiPrime can be used to achieve streamlined and efficient in vivo correction of a pathogenic mutation in the brain of a mouse model of KIF1A-associated neurological disorder. We provide a webserver for OptiPrime ( https://optipri.me/ ) as a community resource.
    DOI:  https://doi.org/10.1038/s41587-026-03261-7
  9. Biofabrication. 2026 Aug 04.
    Human iPSC-derived vascularized organoids: Strategy-based insights from 2D endothelial cells to 3D blood vessel organoids.
    Seo-Yeon Kong, Da-Hyun Kim.
      Organoids derived from human pluripotent stem cells (PSCs) have emerged as powerful in vitro models for studying development, disease, and therapeutic responses, yet their lack of functional vasculature limits growth, maturation, and physiological relevance. Early vascularization strategies relied on human umbilical vein endothelial cells, which lack organ-specific identity and introduce donor variability. The field is now undergoing a paradigm shift toward PSC-derived vasculature, which offers patient-specific, and developmentally stage-matched endothelium with PSC-derived organoids. This review summarizes current strategies for organoid vascularization, with emphasis on both human PSC-derived 2D endothelial cells (EC) and 3D blood vessels. Approaches relying on co-aggregation of differentiated ECs with organ-specific populations or external endothelial coating of pre-formed organoids. These improved survival and functional maturation but remain limited in spatial organization and perfusability. The advances have incorporated pre-formed vascular spheroids and iPSC-derived blood vessel organoids, which can be respectively fused with lineage-specific organoids to generate vascularized assembloids to enhance vascular architecture and tissue maturation. This review further highlights engineering the microenvironment to promote the formation of vascular niche, such as hypoxia modulation, transcriptional regulation, signaling transduction, and extracellular matrix engineering. In addition, we discuss the current limitations as well as future directions of vascularized organoids, including the unmet need for developing tissue-specific ECs, improved engraftment following transplantation, and organ-on-a-chip platforms. Collectively, integrating iPSC-derived vasculature within organoids provides a central framework toward physiologically relevant, perfusable tissues and expands the translational utility of organoid technologies for disease modeling and therapeutic development.
    Keywords:  Blood vessel organoid; Disease modeling; Endothelial cells; Organoid; Vascularization
    DOI:  https://doi.org/10.1088/1758-5090/ae94b5
  10. Dev Cell. 2026 Aug 13. pii: S1534-5807(26)00281-9. [Epub ahead of print]
    Systematic differences in protein stability underlie species-specific developmental tempo.
    Mitsuhiro Matsuda, Henrik M Hammarén, Jorge Lázaro, Mikhail M Savitski, Miki Ebisuya.
      Human embryonic development proceeds more slowly than in mice. The segmentation clock offers a tractable model for studying species-specific developmental tempo, as its oscillation period in human induced presomitic mesoderm (iPSM) cells is approximately twice that of mouse. While the core clock gene HES7 exhibits slower protein degradation in human cells, it remains unclear whether such cross-species differences in protein stability reflect a general principle. Here, we perform a dynamic stable isotope labeling of amino acids in cell culture (SILAC)-based proteomic analysis of ∼5,000 proteins in human and mouse iPSM, and we uncover a broad trend of slower protein degradation in human cells, regardless of subcellular localization or degradation pathways. Moreover, inhibition of glycolysis in mouse iPSM partially phenocopies the human protein stability profile, and modulation of protein stability alters the tempo of both the segmentation clock and cellular differentiation. Our findings establish protein stability, with systematic differences across species, as a key mediator linking metabolism to developmental tempo.
    Keywords:  SILAC proteomics; allochrony; cross-species comparison; developmental tempo; metabolism; protein stability; segmentation clock
    DOI:  https://doi.org/10.1016/j.devcel.2026.07.012
  11. Dev Cell. 2026 Aug 13. pii: S1534-5807(26)00283-2. [Epub ahead of print]
    Proteasome-dependent protein degradation shapes developmental tempo in mouse and human neural progenitors.
    Shota Nakanoh, Despina Stamataki, Lorena Garcia-Perez, Chiara Azzi, Hayley L Carr, Alexandra Pokhilko, Loukik Doshi, Giulia L M Boezio, Hilary Knowles, Adriana Lamas Bancalari, Manuela Melchionda, Lu Yu, Steven Howell, Mark Skehel, David Oxley, Simon Andrews, James Briscoe, Teresa Rayon.
      The pace of embryonic development differs between mammalian species, yet the molecular basis for this remains unknown. By comparing protein dynamics in mouse and human neural progenitors (NPs), we show that protein turnover is faster in mouse NPs, driven by higher rates of protein synthesis and degradation. Human NPs exhibit longer protein half-lives, reduced proteasomal activity, and lower proteasome abundance. These differences persist in post-mitotic neurons and are also observed in the embryonic spinal cord in vivo. Pharmacological inhibition of proteasomal activity slows differentiation in mouse NPs. Conversely, enhancing proteasomal activity accelerates neuronal output in human NPs. Moreover, accelerating the degradation of the key transcriptional repressor IRX3 in mouse NPs speeds the activation of its target gene. Together, these results provide evidence that species-specific regulation of proteasome-mediated proteolysis influences the timing of neural development and suggest that evolutionary tuning of proteasomal activity contributes to differences in embryonic developmental pace.
    Keywords:  UPS; developmental tempo; dynamic SILAC proteomics; gene regulatory network; neural progenitors; post-transciptional regulation; proteasome; protein degradation; proteostasis; spinal cord; stem cells; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.devcel.2026.07.014
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