bims-pideca 2026-04-05 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2026–04–05
nineteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU

Targeted Therapies in Infantile Hemangiomas and Vascular Malformations: From β-Blockers to PI3K/AKT/mTOR Inhibitors.
Untargeted metabolomic profiling reveals mTORC1-dependent regulation of amino acid utilization in lymphatic endothelial cells.
Cooperative roles of class IA PI3K isoforms in translocation-related sarcoma cell survival and proliferation.
Single-cell morphodynamical trajectories enable prediction of gene expression accompanying cell state change.
Basal phosphorylation of SHIP1 by Lyn suppresses proinflammatory signaling in the absence of a phagocytic synapse.
Topography-aware optimal transport for alignment of spatial omics data.
Molecular and structural mechanisms of nutrient sensing in the mTORC1 pathway.
The impact of package selection and versioning on single-cell RNA-seq analysis.
Insulin-stimulated glucose uptake is impaired in senescent human adipocytes.
Genome-wide profiling identifies the genetic dependencies of cell death following EGFR inhibition.
Delivery of Pleckstrin-Homology Domains Suppresses PI3K/Akt Signaling and Breast Cancer Metastasis.
HR3/RORα-mediated cholesterol sensing regulates TOR signaling.
Validated GMP banking of a new set of genomically stable induced pluripotent stem cell lines using single-cell passaging.
Regulation of STK38 by autophagy governs YAP1 activity during paligenosis.
S-SELeCT: a human-evolved serine integrase system for efficient large-cargo genome integration.
Bridging population and cell: modelling complex diseases with human induced pluripotent stem cells.
Redefining cancer drivers with tissue-specific context.
Single-cell and spatial profiling in cancer biology and clinical oncology.
Feeder-Free Generation of Lymphatic Endothelial Cells from Human Induced Pluripotent Stem Cells.

J Cell Mol Med. 2026 Apr;30(7): e71103

Targeted Therapies in Infantile Hemangiomas and Vascular Malformations: From β-Blockers to PI3K/AKT/mTOR Inhibitors.

Hubert Arasiewicz, Michal Dec.

  Vascular tumours and malformations encompass infantile hemangiomas (IHs) and genetically driven vascular malformations with distinct natural histories and therapeutic vulnerabilities. The discovery that the non-selective beta-blocker propranolol induces rapid regression of proliferating IHs established the first widely adopted systemic pharmacologic therapy in vascular anomaly care and provided a clinical proof-of-concept that targeting lesion-specific endothelial biology can alter disease course. In parallel, recurrent somatic variants affecting PI3K/AKT/mTOR (e.g., PIK3CA, TEK/TIE2, AKT1) and RAS/MAPK (e.g., KRAS, NRAS) signalling have reframed many malformations as mosaic disorders amenable to targeted inhibition with agents such as sirolimus, alpelisib, AKT inhibitors and MEK inhibitors. This review synthesizes translational mechanisms, clinical evidence and safety considerations for beta-blockers and emerging targeted therapies, emphasizing lesion phenotype, timing of intervention and molecular stratification as determinants of response. We highlight current limitations, including toxicity, durability and pathway escape, and outline future directions for precision therapy and genotype-guided trial design in vascular anomalies.

Keywords:  PI3K/AKT/mTOR; RAS/MAPK; infantile hemangioma; precision medicine; targeted therapy; vascular malformations

DOI:  https://doi.org/10.1111/jcmm.71103
Vascul Pharmacol. 2026 Apr 01. pii: S1537-1891(26)00029-7. [Epub ahead of print] 107609

Untargeted metabolomic profiling reveals mTORC1-dependent regulation of amino acid utilization in lymphatic endothelial cells.

Jie Zhu, Felix Darko, Fei Han, Summer Simeroth, Lingjun Li, Haiwei Gu, Pengchun Yu.

  The lymphatic vascular system plays essential roles in tissue fluid drainage, dietary fat absorption and transport, and immune cell trafficking. To support these physiological functions, the lymphatic vasculature forms an extensive and highly organized network throughout the body. We recently discovered that the mechanistic target of rapamycin complex 1 (mTORC1), with RAPTOR as an indispensable component, directs glycolysis and glutaminolysis in lymphatic endothelial cells (LECs) to promote lymphatic vessel formation. However, the role of mTORC1 in regulating LEC metabolism remains incompletely understood. Here, by conducting untargeted metabolomic profiling of control and RAPTOR-deficient LECs, we uncover a global impact of mTORC1 inhibition on amino acid utilization. Specifically, RAPTOR deficiency impairs the conversion of glutamine to glutamic acid, resulting in decreased levels of glutamic acid and aspartic acid, as well as reduced abundance of N-acetyl-glutamic acid and N-acetyl-aspartic acid-two metabolites unexpectedly detected in LECs. Integrated metabolomic and transcriptomic analyses further reveal that impaired glutaminolysis in RAPTOR-depleted LECs is accompanied by increased intracellular asparagine, arginine, and metabolites associated with arginine catabolism, potentially driven by upregulation of their respective transporters. In addition, RAPTOR depletion results in abnormal accumulation of branched-chain amino acids (BCAAs) and other essential amino acids primarily involved in protein synthesis. Mechanistically, our data suggest that defective BCAA catabolism and impaired translational control contribute to these metabolic alterations. Collectively, these findings reveal an important role of mTORC1 signaling in coordinating amino acid utilization and suggest that this regulation is critical for lymphatic vessel formation.

Keywords:  Amino acid catabolism; Amino acid transporters; Essential amino acids; Lymphatic endothelial cells; Nonessential amino acids; RAPTOR; mTORC1

DOI:  https://doi.org/10.1016/j.vph.2026.107609
Cancer Res Commun. 2026 Mar 31.

Cooperative roles of class IA PI3K isoforms in translocation-related sarcoma cell survival and proliferation.

Sho Isoyama, Naomi Tamaki, Yutaka Noguchi, Hiroki Shinchi, Takeshi Suzuki, Makoto Hirata, Kotoe Katayama, Hidewaki Nakagawa, Koichi Matsuda, Shin-Ichi Yaguchi, Koji Ueda, Shingo Dan.

Among class I phosphatidylinositol 3-kinase (PI3K) isoforms, the isoform that predominantly regulates proliferation and survival in cancer dependent on PI3K signaling differs according to the genetic background and lineage of origin. We previously reported that translocation-related sarcomas (TRSs) such as synovial sarcoma and Ewing sarcoma are highly susceptible to pan-class I PI3K inhibitors, but the dominant isoform remains unclear. To address this issue, we examined the roles of each PI3K isoform in TRS cells. Neither class I PI3K isoforms nor PI3K-related genes in sarcoma cell lines including TRS, exhibited common mutations. Selective inhibition of PI3Kα moderately suppressed Akt/mTOR signaling, leading to growth inhibition and apoptosis, whereas inhibiting PI3Kβ or PI3Kδ alone had no effect. Interestingly, inhibition of PI3Kα together with PI3Kβ and/or PI3Kδ significantly enhanced the apoptosis induction versus PI3Kα inhibition alone. In contrast, carcinoma cell lines did not undergo apoptosis upon PI3K inhibition, except for PIK3CA-mutated cell lines. In those cell lines, PI3Kα inhibition alone significantly induced apoptosis with no enhancement in simultaneous inhibition of PI3K isoforms. Mechanistically, while PI3Kα primarily mediated Akt/mTOR signaling in TRS cells, PI3Kβ and PI3Kδ compensated for the Akt/mTOR signaling when PI3Kα was inhibited. Simultaneous inhibition of PI3Kα, PI3Kβ and PI3Kδ was more potent than individual inhibition against TRS cells in a mouse xenograft model. These findings suggest that PI3Kα is the dominant isoform, whereas PI3Kβ and PI3Kδ cooperate with PI3Kα in cell survival, which appears to be a characteristic feature of TRS cells. Thus, triple-isoform inhibition might represent an effective therapy for TRSs.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0787
Cell Syst. 2026 Apr 02. pii: S2405-4712(26)00049-9. [Epub ahead of print] 101567

Single-cell morphodynamical trajectories enable prediction of gene expression accompanying cell state change.

Jeremy Copperman, Ian C Mclean, Sean M Gross, Jalim Singh, Vaibhav Murthy, Young Hwan Chang, Alexander E Davies, Daniel M Zuckerman, Laura M Heiser.

  Extracellular signals induce changes to molecular programs that modulate cellular phenotypes, but the connection between dynamically adapting phenotypic states and the molecular programs that define them is not well understood. Here, we develop data-driven models of single-cell phenotypic responses by linking gene transcription levels to "morphodynamics"-changes in cell morphology and motility observable in single-cell trajectories extracted from time-lapse image data. The single-cell trajectories enable a computational approach to map live-cell dynamics to snapshot gene transcript levels, which we term MMIST, molecular and morphodynamics-integrated single-cell trajectories. MMIST identifies a cell state landscape bound by epithelial and mesenchymal endpoints, with distinct sequences of intermediates. This analysis predicts expression of thousands of RNA transcripts through extracellular signal-induced epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) with near-continuous time resolution. The MMIST framework leverages true single-cell dynamical behavior to generate molecular-level omic inferences and is broadly applicable across biological domains, imaging approaches, and molecular snapshot data.

Keywords:  EMT; Markov model; cell state; ligand response; morphodynamics; single-cell dynamics

DOI:  https://doi.org/10.1016/j.cels.2026.101567
J Immunol. 2026 Mar 17. pii: vkaf372. [Epub ahead of print]215(3):

Basal phosphorylation of SHIP1 by Lyn suppresses proinflammatory signaling in the absence of a phagocytic synapse.

S Erandika Senevirathne, William K Kanagy, Charlotte R Hemmila, Joseph T Greene, Andrew T Rajczewski, Richard T Cattley, Whitney L Swanson, Silvia Toledo Ramos, Myra G Nunez, Siyu Jin, William F Hawse, Tanya S Freedman.

  Microscale engagement of the hemi-immunoreceptor tyrosine-based activation motif-containing receptor Dectin-1 by fungal particles activates Src-family kinases (SFKs) and Syk, drives second-messenger generation, and induces downstream Erk and Akt signaling and proinflammatory responses in macrophages. To avoid inappropriate activation in the absence of a pathogenic threat, macrophages restrict signaling in response to low-valency ligands. To examine how SFKs regulate this sensitivity threshold, we compared signaling induced by pharmacological SFK activation with signaling triggered by depleted zymosan, a high-valency β-glucan particle that engages Dectin-1 to form a phagocytic synapse. We found that particulate engagement of Dectin-1 protected the inhibitory ITIM-associated phosphatase SHIP1 from phosphorylation by SFKs, allowing robust activation of Erk and Akt and proinflammatory induction. In contrast, receptor-independent SFK activation induced phosphorylation of SHIP1 and failed to amplify signaling downstream of PLCγ2 and PI3K. Although multiple SFKs could phosphorylate SHIP1, Lyn uniquely maintained the basal set-point of SHIP1 phosphorylation, thereby keeping PIP3 levels low and suppressing basal Erk and Akt signaling. This Lyn-dependent regulation was essential for suppressing Akt activation and balancing signaling through the Erk and Akt pathways in the absence of a phagocytic synapse. In contrast, antimicrobial responses to particulate stimuli, including second-messenger signaling, Erk/Akt, and proinflammatory outputs, did not strictly require Lyn expression. These findings highlight the unique role of Lyn in limiting spurious proinflammatory signaling and shed light on a mechanism by which macrophages selectively respond to high-valency particulate ligands that override this basal inhibitory program.

Keywords:  molecular biology; monocytes/macrophages; protein kinases/phosphatases; signal transduction; transgenic/knockout mice

DOI:  https://doi.org/10.1093/jimmun/vkaf372
Cell Rep Methods. 2026 Mar 30. pii: S2667-2375(26)00073-1. [Epub ahead of print] 101373

Topography-aware optimal transport for alignment of spatial omics data.

Francesco Ceccarelli, Pietro Liò, Julio Saez-Rodriguez, Sean B Holden, Jovan Tanevski.

  Recent advances in spatial omics technologies have provided unprecedented insight into tissue spatial organization, but challenges remain in aligning spatial slices and integrating complementary single-cell and spatial data. Here, we propose TOAST (topography-aware optimal alignment of spatially resolved tissues), an optimal transport (OT)-based framework that extends the classical fused Gromov-Wasserstein (FGW) objective to more comprehensively model the heterogeneity of local molecular interactions. By introducing "spatial coherence," quantified through the entropy of local neighborhoods, and "neighborhood consistency," which preserves the expression profiles of neighboring spots, TOAST's objective function improves the alignment of spatially resolved tissue slices and the mapping between single-cell and spatial data. Through comprehensive evaluations, we demonstrate that our method consistently outperforms traditional FGW and other OT-based alignment methods. By integrating spatial constraints into OT, our framework provides a principled approach to enhance the biological interpretability of spatially resolved omics data and facilitate multimodal data integration.

Keywords:  CP: computational biology; CP: systems biology; fused Gromov-Wasserstein; multimodal data integration; optimal transport; spatial alignment; spatial proteomics; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.crmeth.2026.101373
Trends Biochem Sci. 2026 Mar 30. pii: S0968-0004(26)00037-X. [Epub ahead of print]

Molecular and structural mechanisms of nutrient sensing in the mTORC1 pathway.

Serim Yang, Tong Bian, Roberto Zoncu.

  Primary nutrient sensors directly bind metabolites and undergo conformational changes that signal through core pathways to coordinate metabolic and cellular outcomes. Sensing of amino acids, lipids, sugars, and nucleotides is critical for the master growth regulatory Ser/Thr kinase, mechanistic target of rapamycin complex 1 (mTORC1), to promote growth and proliferation. Systematic proteomic and bioinformatic studies have accelerated the discovery of primary nutrient sensors upstream of mTORC1, whereas structural biology has shed light on how binding to their cognate metabolites triggers mTORC1-dependent signaling responses. This review focuses on recently reported amino acid and lipid sensors upstream of mTORC1 and highlights structural and functional features of these sensors that illuminate fundamental principles of nutrient detection and signal transduction.

Keywords:  CASTOR1; LYCHOS; amino acid sensors; cholesterol sensors; metabolites; primary nutrient sensor

DOI:  https://doi.org/10.1016/j.tibs.2026.02.009
Cell Syst. 2026 Mar 27. pii: S2405-4712(26)00042-6. [Epub ahead of print] 101560

The impact of package selection and versioning on single-cell RNA-seq analysis.

Joseph M Rich, Lambda Moses, Pétur Helgi Einarsson, Kayla Jackson, Laura Luebbert, A Sina Booeshaghi, Sindri Antonsson, Delaney K Sullivan, Nicolas Bray, Páll Melsted, Lior Pachter.

  Standard single-cell RNA sequencing (scRNA-seq) workflows convert raw reads into cell-gene count matrices and then perform filtering, highly variable gene selection, dimensionality reduction, clustering, and differential expression analysis. Seurat and Scanpy are the most widely used implementations of these workflows and are generally assumed to yield similar results. Here, we examine the underlying algorithms of both packages and show that their outputs differ substantially across multiple analytic steps. The magnitude of Seurat-Scanpy differences is comparable to the variability introduced by sequencing fewer than 5% of reads or analyzing fewer than 20% of cells. We further find that software version changes can alter results, particularly in differential expression. Our findings underscore the need for users to critically evaluate analysis tools and for developers to prioritize transparency and reproducibility.

Keywords:  Scanpy; Seurat; open source software; single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.cels.2026.101560
Front Endocrinol (Lausanne). 2026 ;17 1795654

Insulin-stimulated glucose uptake is impaired in senescent human adipocytes.

Ida Alexandersson, Henrik Palmgren, Martin Uhrbom, Jan Oscarsson, Jeremie Boucher.

   Background: Cell senescence, a state of cell cycle arrest induced by intrinsic or extrinsic stress, is linked to aging and aging-associated diseases. Senescence markers are elevated in adipose tissue with age and in obesity. Recently, it was shown that human mature adipocytes can undergo senescence in response to hyperinsulinemia. However, the functional consequences of adipocyte cell senescence remain poorly understood.
Methods: To study the impact of cellular senescence on human adipocyte function, we induced senescence in differentiated primary human preadipocytes (referred to as human adipocytes) using nutlin-3a, doxorubicin and etoposide. Expression of senescence markers, insulin receptor signaling, response to lipolytic stimuli and insulin mediated glucose uptake were investigated.
Results: The senescence-inducing compounds increased expression of senescence markers p21, p53, activity of senescence-associated β-galactosidase (SA-βgal) and secretion of senescence-associated secreted factors (SASP). We showed that insulin-stimulated glucose uptake, but not basal glucose uptake, was significantly reduced in senescent adipocytes. Insulin receptor signaling was largely unaffected, while expression of insulin receptor signaling proteins and especially GLUT4 expression were reduced. Expression of some adipocyte marker genes, including ADIPOQ, LEP, PNPLA2, LIPE and PPARγ2, and secretion of adiponectin were reduced in the senescent adipocytes. In contrast, lipolytic capacity of senescent adipocytes was largely unaffected.
Conclusions: Our findings indicate that cellular senescence impairs insulin-stimulated glucose uptake but not lipolytic capacity; changes that may contribute to impaired glucose control and ectopic fat accumulation.

Keywords:  adipocytes; cellular senescence; glucose uptake; insulin sensitivity; lipolysis

DOI:  https://doi.org/10.3389/fendo.2026.1795654
J Biol Chem. 2026 Apr 01. pii: S0021-9258(26)00284-X. [Epub ahead of print] 111414

Genome-wide profiling identifies the genetic dependencies of cell death following EGFR inhibition.

Sydney A Porto, Gavin A Birdsall, Nicholas W Harper, Megan E Honeywell, Scott M Leighow, Tiana E Naylor, Kelly M Ward, Mika K Wesley, Justin R Pritchard, Michael J Lee.

  EGFR is a proto-oncogene that is mutationally activated in a variety of cancers. Small molecule inhibitors targeting EGFR can effectively slow the progression of disease, and in some settings, these drugs even cause dramatic tumor regression. However, responses to EGFR inhibitors are rarely durable, and the mechanisms contributing to response variation remain unclear. In particular, several distinct mechanisms have been proposed to explain how EGFR inhibition activates cell death, and a consensus has yet to emerge. In this study, we use functional genomics with specialized analyses to infer how genetic perturbations affect the drug-induced death rate. Our data clarify that inhibition of PI3K signaling drives the lethality of EGFR inhibition. Inhibition of other pathways downstream of EGFR, including the RAS-MAPK pathway, promotes growth suppression but not the lethal effects of EGFR inhibitors. Taken together, our study provides a "reference map" for the genome-wide genetic dependencies of lethality in response to EGFR inhibitors.

Keywords:  cancer therapy; cell death; drug action; epidermal growth factor receptor (EGFR); functional genomics; lung cancer; systems biology

DOI:  https://doi.org/10.1016/j.jbc.2026.111414
Adv Sci (Weinh). 2026 Mar 30. e18339

Delivery of Pleckstrin-Homology Domains Suppresses PI3K/Akt Signaling and Breast Cancer Metastasis.

Matthew Eason, Anindya Sen, Suhan Cho, Se Jong Lee, Keyata Thompson, Md Musavvir Mahmud, Poornima Dubey, Talia Guardia, Anthony Kim, Stuart Martin, Nathan Wright, Konstantinos Konstantopoulos, Aikaterini Kontrogianni-Konstantopoulos.

  Current cancer therapies inhibit tumor growth but fail to target metastatic dissemination. Obscurin (720-870 kDa), a giant signaling protein localizing to the breast epithelial cell membrane, is a metastasis suppressor commonly lost in breast cancer. Obscurin loss upregulates the oncogenic PI3K/Akt axis. While restoring obscurin expression is crucial from a translational standpoint, it poses major challenges due to its immense size. Herein, we overcome this hurdle by delivering a mini-obscurin-comprising the obscurin-pleckstrin homology (PH) domain, which is ∼50-times smaller than the full-length protein-into aggressive breast cancer cells via adenovirus and lipid nanoparticles. Mechanistically, the obscurin-PH-domain interacts with the PI3K-p85 regulatory subunit. Membrane-targeted obscurin-PH sequesters p85, suppressing PI3K/Akt activity. p85-sequestration eliminates filopodia, hampering migration and adhesion to pre-metastatic niche extracellular matrix substrates. This intervention further eradicates invadopodia and reduces matrix metalloproteinase expression, blocking invasion, dissemination, and metastasis. We recapitulate this phenotype using the structurally homologous kalirin and PLCγ1 PH-domains and ultimately uncover a family of nine PH-domains that may act as PI3K inhibitors, unified by the "p85 inhibitory metastasis suppressor" (PIMS) motif, mediating this effect. This work engineers a first-in-class group of non-chemical PI3K inhibitors, uniquely targeting the PI3K-p85 subunit, galvanizing novel gene therapies for treating metastatic breast cancer.

Keywords:  PI3K inhibitors; PI3K/Akt signaling; breast cancer; metastasis suppressors; obscurin; pleckstrin homology domains

DOI:  https://doi.org/10.1002/advs.202518339
Nat Commun. 2026 Mar 30.

HR3/RORα-mediated cholesterol sensing regulates TOR signaling.

Mette Lassen, Keith Pardee, Ivan Bradic, Lisa H Pedersen, Olga Kubrak, Nadja Ahrentløv, Sebastian Clancy, Takashi Koyama, Aleksandar Necakov, Suya Liu, Arnis Kuksis, Gilles Lajoie, Aled Edwards, Aurelio A Teleman, Martin R Larsen, Henry M Krause, Michael J Texada, Kim Rewitz.

Cells and organisms adjust their growth based on the availability of cholesterol, which is essential for cellular functions. However, the mechanisms by which cells sense cholesterol levels and translate these into growth signals are not fully understood. We report that cholesterol rapidly activates the master growth-regulatory TOR pathway in Drosophila tissues. We identify the nuclear receptor HR3, an ortholog of mammalian RORα, as an essential factor in cholesterol-induced TOR activation. We demonstrate that HR3 binds cholesterol and promotes TOR-pathway activation through a non-genomic mechanism acting upstream of the Rag GTPases while also restraining longer-term responses through genomic regulation. We also find that RORα is necessary for cholesterol-mediated TOR activation in human cells, suggesting that HR3/RORα-mediated signaling represents a conserved mechanism for cholesterol sensing that couples cholesterol availability to TOR-pathway activity. These findings advance our understanding of how cholesterol influences cell growth, with implications for cholesterol-related diseases and cancer.

DOI: https://doi.org/10.1038/s41467-026-71059-x
Cytotherapy. 2026 Feb 24. pii: S1465-3249(26)00082-4. [Epub ahead of print]28(6): 102120

Validated GMP banking of a new set of genomically stable induced pluripotent stem cell lines using single-cell passaging.

Björn Hiller, Francois Hafezi, Jens Lichte, Noah Henschel, Claudia Träger, Melanie Hühne, Anna Gamerschlag, Thomas Berger, Soraia Martins, Daniel Terheyden-Keighley, Elitsa Borisova, Davood Sabour, Agnes Beermann, Gesine Kogler, Andrea Meffert, Boris Greber.

  Single-cell passaging of induced pluripotent stem cells (iPSCs) has historically been discredited, as it may risk mutations. Here, however, in combination with Rho kinase inhibition and based on stringent quality control, we successfully validate a corresponding iPSC banking process under Good Manufacturing Practice (GMP) conditions. The underlying culture system features enhanced consistency, sustains genomic integrity in the resulting cell lines, and enables excellent priming for gene editing and directed differentiation. The process, as well as the resulting GMP iPSC lines, will provide a robust foundation for clinical manufacturing.

Keywords:  GMP cell banking; Human iPS cells; Rho kinase inhibition; directed differentiation; single-cell passaging

DOI:  https://doi.org/10.1016/j.jcyt.2026.102120
Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2517488123

Regulation of STK38 by autophagy governs YAP1 activity during paligenosis.

Yongji Zeng, Yang-Zhe Huang, Qing Kay Li, Raymond Ho, Steven J Bark, Spencer G Willet, Richard J DiPaolo, Jason C Mills.

  Paligenosis is a conserved cellular plasticity program that allows mature cells to reenter the cell cycle in response to tissue injury. Paligenosis progresses via three stages: autodegradation (with dramatic increase in autophagy and lysosomes), induction of metaplastic or fetal-like genes, and cell cycle entry. Hippo signaling, particularly the downstream effector YAP1, regulates cellular plasticity, but its role in paligenosis has not been studied. Here, we examine YAP1 dynamics during paligenosis in digestive-enzyme-secreting chief cells from the mouse stomach. We identified Serine/Threonine Kinase 38 (STK38) as a noncanonical YAP1 kinase that phosphorylates and deactivates YAP1 in uninjured chief cells. During paligenosis, STK38 was degraded by autophagy in stage 1, dephosphorylating and activating YAP1. YAP1 activation was necessary and sufficient for paligenosis-driven conversion of chief cells into metaplastic, proliferating progenitors. Additionally, we show that STK38, like canonical Hippo kinases, interacts with Neurofibromatosis Type 2 (Merlin), a scaffold that recruits Hippo kinases to phosphorylate YAP1. We also observed the same pattern of YAP1 induction via autophagic destruction of STK38 in other tissues and cell types, suggesting injury-induced activation of autophagy in differentiated cells during tissue damage may be a more general feature by which Hippo effectors induce plasticity for regeneration.

Keywords:  Hippo pathway; redifferentiation; reprogramming

DOI:  https://doi.org/10.1073/pnas.2517488123
Nucleic Acids Res. 2026 Mar 19. pii: gkag286. [Epub ahead of print]54(6):

S-SELeCT: a human-evolved serine integrase system for efficient large-cargo genome integration.

Alfonso P Farruggio, Lin Jiang, Karen Duong, Cynthia Nguyen, Razan Kaddoura, Ruby Tsai.

As a consequence of their sizes, many loss-of-function genetic mutations fall within large genes. A major gene-therapy tool that could be used to solve large swaths of the genetic diseases that result from these inherited mutations is large-fragment knock-in. I.e. instead of attempting to create separate treatments for each and every location that these mutations occur in, large groups of patients could be aided via a single safe-harbor integration of the full-length coding sequence. Toward this goal, we have created a set of early stage gene-editing enzymes that can help mediate large cargo integration at a safe harbor locus in human cells. When expressed in stable lines, our S-SELeCT (Site-Specific Large Cargo Targeting) integrase fusions can facilitate integration of a 10 kb plasmid at frequencies up to 32%, and when delivered transiently via plasmid transfection, we were able to achieve up to 13% knock-in. These are the first serine integrase enzymes that have been evolved fully in human cells and the first to recognize an endogenous symmetric non-pseudosite-the first true human serine integrase attachment site.

DOI: https://doi.org/10.1093/nar/gkag286
Eur J Hum Genet. 2026 Mar 31.

Bridging population and cell: modelling complex diseases with human induced pluripotent stem cells.

Eva S van Zanten, Elizabeth A Loehrer, Joyce B J van Meurs, Roberto Narcisi, Joost H Gribnau, Raymond A Poot, Hieab H H Adams.

  Induced pluripotent stem cells (iPSCs) have emerged as a powerful tool in biomedical research, enabling the study of cellular function and early disease mechanisms within patient-specific genetic contexts. Traditionally, iPSCs have been used to model monogenic diseases, where highly penetrant variants produce robust cellular phenotypes detectable in few cell lines. Recent advances in scalability and standardisation now enable systematic comparisons across many donors. This development is particularly relevant for complex diseases, which are driven by numerous genetic variants with small individual effects and therefore require population-scale designs to resolve genotype-phenotype relationships. However, several limitations of iPSC technology continue to challenge the reliability and reproducibility of such studies, constraining their translational relevance. Here, we review the challenges and opportunities of using iPSCs to model complex diseases, structured around three key themes: detecting subtle effects, modelling environmental context, and expanding genetic diversity.

Keywords:  Complex diseases; Disease modelling; Functional genomics; Genetic variation; Induced pluripotent stem cells

DOI:  https://doi.org/10.1038/s41431-026-02071-4
Cancer Cell. 2026 Apr 02. pii: S1535-6108(26)00161-3. [Epub ahead of print]

Redefining cancer drivers with tissue-specific context.

Maria Kalyva, Nicholas McGranahan.

In this issue of Cancer Cell, Bandlamudi and colleagues analyze over 50,000 tumors spanning 64 cancer types, revealing how tissue context dictates the prevalence and evolutionary timing of somatic driver alterations. Their findings underscore the need to move away from a purely gene-centric view of oncology toward a context-aware framework.

DOI: https://doi.org/10.1016/j.ccell.2026.03.007
Nat Cancer. 2026 Apr 03.

Single-cell and spatial profiling in cancer biology and clinical oncology.

Chris J Frangieh, Joy Linyue Fan, Johannes C Melms, Parin Shah, Elham Azizi, Benjamin Izar.

Multiple single-cell and spatial genomics tools have transformed our ability to deconvolve intricate diseases, including cancer. Analysis of complex, multimodal data has provided insights into genomics, cellular states and interactions in tumor ecosystems, enabling the dissection of salient biology and expanding our understanding of drug response, resistance and target discovery. However, several challenges remain before these methods can achieve their full clinical potential. Here, we discuss opportunities, barriers and potential solutions, including sample acquisition and preservation approaches, profiling methods and analytical tools for heterogeneous populations, and we provide recommendations for robust, reproducible use of these technologies in clinical settings.

DOI: https://doi.org/10.1038/s43018-026-01142-1
bioRxiv. 2026 Mar 23. pii: 2026.03.19.712968. [Epub ahead of print]

Feeder-Free Generation of Lymphatic Endothelial Cells from Human Induced Pluripotent Stem Cells.

Aditi Prasad, Shrey Patel, Simon Ng, Clifford Z Liu, Bruce D Gelb.

Abstract: The lymphatic system is essential for maintaining fluid homeostasis, lipid transport and supporting immune function. Despite its central role in health and disease, advancements in understanding human lymphatic vasculature has been constrained, in part because primary human LECs are difficult to access and study in disease-relevant contexts. This study describes an efficient and scalable feeder-free method to differentiate human iPSCs into lymphatic endothelial cells (LECs) that are transcriptionally and phenotypically similar to primary fetal LECs. An iPSC-derived LEC system overcomes a drawback of primary cells by enabling precise genetic perturbations, supporting study of lymphatic diseases of interest in a human context. By grounding our approach in in vivo stages of lymphangiogenisis, we describe a staged protocol that recapitulates the key milestones of lymphatic development. We first adapted a published method to differentiate human iPSCs into venous endothelial cells (VECs) and then initiate transdifferentiation of VECs into LECs. Using immunocytochemistry, qPCR, as well as flow cytometry, we demonstrated expression of lymphatic-specific markers in the differentiated population. We further characterized our induced VECs (iVECs) and LECs (iLECs) through bulk RNA sequencing analysis and compared the populations to pseudobulk VEC and LEC transcriptomic datasets generated from human fetal heart endothelia at 12, 13 and 14 weeks of gestation. Through this work, we expanded the repertoire of approaches for accessing LECs, with the goal of accelerating discoveries in lymphatic biology and therapeutics.
Abstract summary image:

DOI: https://doi.org/10.64898/2026.03.19.712968