bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2025–01–12
thirty papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. The Zika virus NS5 protein binds HSP90 to suppress EGF-induced Akt signaling and trophoblast cell migration.
  2. Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations.
  3. BRAF V600 and ErbB inhibitors directly activate GCN2 in an off-target manner to limit cancer cell proliferation.
  4. Covalent inhibitors of the RAS binding domain of PI3Kα impair tumor growth driven by RAS and HER2.
  5. PTMNavigator: interactive visualization of differentially regulated post-translational modifications in cellular signaling pathways.
  6. Mechanical Stretch Control of Adipocyte AKT Signaling and the Role of FAK and ROCK Mechanosensors.
  7. High glucose couples DJ-1 with PTEN to activate PDGFRβ for renal proximal tubular cell injury.
  8. Soft Modes as a Predictive Framework for Low Dimensional Biological Systems across Scales.
  9. Mitochondrial phosphatase PPTC7 promotes EGFR recycling by facilitating VPS4A endosomal localization.
  10. Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation.
  11. RHEB neddylation by the UBE2F-SAG axis enhances mTORC1 activity and aggravates liver tumorigenesis.
  12. Mechanism-guided engineering of a minimal biological particle for genome editing.
  13. A signaling inspired synthetic toolkit for efficient production of tyrosine phosphorylated proteins.
  14. MatriCom: a scRNA-Seq data mining tool to infer ECM-ECM and cell-ECM communication systems.
  15. Innate versus adoptive competence: the controlled distribution of signalling receptors extends the concept of competence.
  16. Galaxy as a gateway to bioinformatics: Multi-Interface Galaxy Hands-on Training Suite (MIGHTS) for scRNA-seq.
  17. Endothelial tip-cell position, filopodia formation and biomechanics require BMPR2 expression and signaling.
  18. The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells.
  19. Transcript-specific enrichment enables profiling of rare cell states via single-cell RNA sequencing.
  20. Perivascular cells function as key mediators of mechanical and structural changes in vascular capillaries.
  21. Phosphorylation of endothelial histone H3.3 serine 31 by PKN1 links flow-induced signaling to proatherogenic gene expression.
  22. Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats.
  23. Hypo-osmotic stress shifts transcription of circadian genes.
  24. PTMVision: An Interactive Visualization Webserver for Post-translational Modifications of Proteins.
  25. NIH sets out to double check biomedical studies.
  26. Unveiling endothelial cell border heterogeneity: VE-cadherin adherens junction stratification by deep convolutional neural networks.
  27. CRISPR-Enabled Autonomous Transposable Element (CREATE) for RNA-based gene editing and delivery.
  28. YAP-driven malignant reprogramming of oral epithelial stem cells at single cell resolution.
  29. Simple quantitation and spatial characterization of label free cellular images.
  30. Ancestry-linked stromal variations impact breast epithelial cell invasion.
  1. Virology. 2024 Dec 28. pii: S0042-6822(24)00394-5. [Epub ahead of print]603 110370
    The Zika virus NS5 protein binds HSP90 to suppress EGF-induced Akt signaling and trophoblast cell migration.
    Nika Hajari, Megan Knoll, Amy Lu, Isaac Barber-Axthelm, Michael Gale.
      Zika virus (ZIKV) infection during pregnancy can cause congenital Zika virus syndrome (CZV), including fetal growth restriction and death. In the developing placenta, trophoblast cells respond to epidermal growth factor (EGF) to migrate into the decidua to facilitate implantation and fetal development. EGF activates the Akt protein kinase, a master regulator of trophoblast cell migration. Akt signaling and stability are dependent on heat shock protein 90 (HSP90), which mediates the maturation of proteins necessary for EGF/Akt signaling. Here we show that ZIKV infection inhibits EGF-mediated Akt activation and downstream signaling to suppress trophoblast migration. The ZIKV non-structural protein 5 (NS5) is sufficient to inhibit trophoblast migration through its binding interaction with HSP90, leading to suppression of Akt phosphorylation and inhibition of EGF-induced trophoblast migration. Thus, ZIKV NS5/HSP90 interactions play a key role in disruption of trophoblast function, revealing an underlying cause of improper placental development and fetal disease.
    Keywords:  Akt; EGF; HSP90; Migration; Nonstructural protein 5 (NS5); PI3K; Placenta; Pregnancy; Trophoblast; Zika virus (ZIKV)
    DOI:  https://doi.org/10.1016/j.virol.2024.110370
  2. Nat Cell Biol. 2025 Jan 06.
    Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations.
    Anupama Hemalatha, Zongyu Li, David G Gonzalez, Catherine Matte-Martone, Karen Tai, Elizabeth Lathrop, Daniel Gil, Smirthy Ganesan, Lauren E Gonzalez, Melissa Skala, Rachel J Perry, Valentina Greco.
      Skin epithelial stem cells correct aberrancies induced by oncogenic mutations. Oncogenes invoke different strategies of epithelial tolerance; while wild-type cells outcompete β-catenin-gain-of-function (βcatGOF) cells, HrasG12V cells outcompete wild-type cells. Here we ask how metabolic states change as wild-type stem cells interface with mutant cells and drive different cell-competition outcomes. By tracking the endogenous redox ratio (NAD(P)H/FAD) with single-cell resolution in the same mouse over time, we discover that βcatGOF and HrasG12V mutations, when interfaced with wild-type epidermal stem cells, lead to a rapid drop in redox ratios, indicating more oxidized cellular redox. However, the resultant redox differential persists through time in βcatGOF, whereas it is flattened rapidly in the HrasG12Vmodel. Using 13C liquid chromatography-tandem mass spectrometry, we find that the βcatGOF and HrasG12V mutant epidermis increase the fractional contribution of glucose through the oxidative tricarboxylic acid cycle. Treatment with metformin, a modifier of cytosolic redox, inhibits downstream mutant phenotypes and reverses cell-competition outcomes of both mutant models.
    DOI:  https://doi.org/10.1038/s41556-024-01574-w
  3. bioRxiv. 2024 Dec 20. pii: 2024.12.19.629301. [Epub ahead of print]
    BRAF V600 and ErbB inhibitors directly activate GCN2 in an off-target manner to limit cancer cell proliferation.
    C Ryland, Nasreen C Marikar, Vu Nguyen, Varuna Nangia, Alicia M Darnell, Matthew G Vander Heiden, Philip Reigan, Sabrina L Spencer.
      Targeted kinase inhibitors are well known for their promiscuity and off-target effects. Herein, we define an off-target effect in which several clinical BRAF V600 inhibitors, including the widely used dabrafenib and encorafenib, interact directly with GCN2 to activate the Integrated Stress Response and ATF4. Blocking this off-target effect by co-drugging with a GCN2 inhibitor in A375 melanoma cells causes enhancement rather than suppression of cancer cell outgrowth, suggesting that the off-target activation of GCN2 is detrimental to these cells. This result is mirrored in PC9 lung cancer cells treated with erlotinib, an EGFR inhibitor, that shares the same off-target activation of GCN2. Using an in silico kinase inhibitor screen, we identified dozens of FDA-approved drugs that appear to share this off-target activation of GCN2 and ATF4. Thus, GCN2 activation may modulate the therapeutic efficacy of some kinase inhibitors, depending on the cancer context.
    DOI:  https://doi.org/10.1101/2024.12.19.629301
  4. bioRxiv. 2024 Dec 20. pii: 2024.12.17.629001. [Epub ahead of print]
    Covalent inhibitors of the RAS binding domain of PI3Kα impair tumor growth driven by RAS and HER2.
    Joseph E Klebba, Nilotpal Roy, Steffen M Bernard, Stephanie Grabow, Melissa A Hoffman, Hui Miao, Junko Tamiya, Jinwei Wang, Cynthia Berry, Antonio Esparza-Oros, Richard Lin, Yongsheng Liu, Marie Pariollaud, Holly Parker, Igor Mochalkin, Sareena Rana, Aaron N Snead, Eric J Walton, Taylor E Wyrick, Erick Aitichson, Karl Bedke, Jacyln C Brannon, Joel M Chick, Kenneth Hee, Benjamin D Horning, Mohamed Ismail, Kelsey N Lamb, Wei Lin, Justine Metzger, Martha K Pastuszka, Jonathan Pollock, John J Sigler, Mona Tomaschko, Eileen Tran, Todd M Kinsella, Miriam Molina-Arcas, Gabriel M Simon, David S Weinstein, Julian Downward, Matthew P Patricelli.
      Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3K's role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block the ability of RAS to activate PI3K activity. These inhibitors have a profound impact on the growth of RAS mutant and also HER2 over-expressing tumors, particularly when combined with other inhibitors of the RAS/MAPK pathway, without causing hyperglycemia.
    DOI:  https://doi.org/10.1101/2024.12.17.629001
  5. Nat Commun. 2025 Jan 08. 16(1): 510
    PTMNavigator: interactive visualization of differentially regulated post-translational modifications in cellular signaling pathways.
    Julian Müller, Florian P Bayer, Mathias Wilhelm, Maximilian G Schuh, Bernhard Kuster, Matthew The.
      Post-translational modifications (PTMs) play pivotal roles in regulating cellular signaling, fine-tuning protein function, and orchestrating complex biological processes. Despite their importance, the lack of comprehensive tools for studying PTMs from a pathway-centric perspective has limited our ability to understand how PTMs modulate cellular pathways on a molecular level. Here, we present PTMNavigator, a tool integrated into the ProteomicsDB platform that offers an interactive interface for researchers to overlay experimental PTM data with pathway diagrams. PTMNavigator provides ~3000 canonical pathways from manually curated databases, enabling users to modify and create custom diagrams tailored to their data. Additionally, PTMNavigator automatically runs kinase and pathway enrichment algorithms whose results are directly integrated into the visualization. This offers a comprehensive view of the intricate relationship between PTMs and signaling pathways. We demonstrate the utility of PTMNavigator by applying it to two phosphoproteomics datasets, showing how it can enhance pathway enrichment analysis, visualize how drug treatments result in a discernable flow of PTM-driven signaling, and aid in proposing extensions to existing pathways. By enhancing our understanding of cellular signaling dynamics and facilitating the discovery of PTM-pathway interactions, PTMNavigator advances our knowledge of PTM biology and its implications in health and disease.
    DOI:  https://doi.org/10.1038/s41467-024-55533-y
  6. Bioengineering (Basel). 2024 Dec 16. pii: 1279. [Epub ahead of print]11(12):
    Mechanical Stretch Control of Adipocyte AKT Signaling and the Role of FAK and ROCK Mechanosensors.
    Tasneem Bouzid, Eunju Kim, Brandon D Riehl, Ruiguo Yang, Viswanathan Saraswathi, Jason K Kim, Jung Yul Lim.
      Adipose tissue in vivo is physiologically exposed to compound mechanical loading due to bodyweight bearing, posture, and motion. The capability of adipocytes to sense and respond to mechanical loading milieus to influence metabolic functions may provide a new insight into obesity and metabolic diseases such as type 2 diabetes (T2D). Here, we evidenced physiological mechanical loading control of adipocyte insulin signaling cascades. We exposed differentiated 3T3-L1 adipocytes to mechanical stretching and assessed key markers of insulin signaling, AKT activation, and GLUT4 translocation, required for glucose uptake. We showed that cyclic stretch loading at 5% strain and 1 Hz frequency increases AKT phosphorylation and GLUT4 translocation to the plasma membrane by approximately two-fold increases compared to unstretched controls for both markers as assessed by immunoblotting (p < 0.05). These results indicate that cyclic stretching activates insulin signaling and GLUT4 trafficking in adipocytes. In the mechanosensing mechanism study, focal adhesion kinase (FAK) inhibitor (FAK14) and RhoA kinase (ROCK) inhibitor (Y-27632) impaired actin cytoskeleton structural formation and significantly suppressed the stretch induction of AKT phosphorylation in adipocytes (p < 0.001). This suggests the regulatory role of focal adhesion and cytoskeletal mechanosensing in adipocyte insulin signaling under stretch loading. Our finding on the impact of mechanical stretch loading on key insulin signaling effectors in differentiated adipocytes and the mediatory role of focal adhesion and cytoskeleton mechanosensors is the first of its kind to our knowledge. This may suggest a therapeutic potential of mechanical loading cue in improving conditions of obesity and T2D. For instance, cyclic mechanical stretch loading of adipose tissue could be explored as a tool to improve insulin sensitivity in patients with obesity and T2D, and the mediatory mechanosensors such as FAK and ROCK may be targeted to further invigorate stretch-induced insulin signaling activation.
    Keywords:  AKT; FAK; GLUT4; ROCK; adipocyte; insulin signaling; mechanical stretch loading
    DOI:  https://doi.org/10.3390/bioengineering11121279
  7. PLoS One. 2025 ;20(1): e0311828
    High glucose couples DJ-1 with PTEN to activate PDGFRβ for renal proximal tubular cell injury.
    Falguni Das, Nandini Ghosh-Choudhury, Balakuntalam S Kasinath, Kumar Sharma, Goutam Ghosh Choudhury.
      High glucose milieu in diabetes induces proximal tubular epithelial cells in the kidney to undergo hypertrophy and matrix protein expansion via Akt/mTORC1 signaling, leading to renal fibrosis. The familial Parkinson's disease protein DJ-1 acts as a driver of Ras-dependent tumorigenesis and protects dopaminergic neurons from apoptosis. But its function and mechanistic basis to regulate renal fibrosis is not clear. Here, we identify DJ-1 as a high glucose-promoted protein in renal proximal tubular epithelial cells. Mechanistic interrogation revealed that DJ-1 formed complex with the lipid phosphatase PTEN in high glucose-stimulated cells, resulting in phosphorylation/activation of Akt and mTORC1. siRNAs against DJ-1 decreased high glucose-stimulated Akt/mTORC1 activation. In contrast, overexpression of DJ-1 mimicked all effects of high glucose. Interestingly, inhibition of DJ-1 blocked high glucose-induced hypertrophy of proximal tubular epithelial cells and, matrix proteins fibronectin and collagen I (α2) expression while overexpression of DJ-1 mimicked the high glucose effects on these phenomena. Previously, we reported a role of PDGFRβ in proximal tubular cell injury. In exploring the mechanism of DJ-1 function, we found that siDJ-1 inhibited high glucose-induced activating and PI 3 kinase docking site tyrosine phosphorylation of PDGF receptor-β (PDGFRβ) to block phosphorylation of PI 3 kinase. Interestingly, overexpression of PTEN mimicked these effects of siDJ-1. Together, our results reveal an important role of DJ-1-PTEN nodal point for PDGFRβ activation during high glucose-induced proximal tubular epithelial cell injury.
    DOI:  https://doi.org/10.1371/journal.pone.0311828
  8. ArXiv. 2024 Dec 18. pii: arXiv:2412.13637v1. [Epub ahead of print]
    Soft Modes as a Predictive Framework for Low Dimensional Biological Systems across Scales.
    Christopher Joel Russo, Kabir Husain, Arvind Murugan.
      All biological systems are subject to perturbations: due to thermal fluctuations, external environments, or mutations. Yet, while biological systems are composed of thousands of interacting components, recent high-throughput experiments show that their response to perturbations is surprisingly low-dimensional: confined to only a few stereotyped changes out of the many possible. Here, we explore a unifying dynamical systems framework - soft modes - to explain and analyze low-dimensionality in biology, from molecules to eco-systems. We argue that this one framework of soft modes makes non-trivial predictions that generalize classic ideas from developmental biology to disparate systems, namely: phenocopying, dual buffering, and global epistasis. While some of these predictions have been borne out in experiments, we discuss how soft modes allow for a surprisingly far-reaching and unifying framework in which to analyze data from protein biophysics to microbial ecology.
  9. J Cell Sci. 2025 Jan 08. pii: jcs.263676. [Epub ahead of print]
    Mitochondrial phosphatase PPTC7 promotes EGFR recycling by facilitating VPS4A endosomal localization.
    Rahul Baroi, Hilal Ahmad Reshi, SubbaReddy Maddika.
      PPTC7 is a mitochondrial phosphatase that is essential for mitochondrial biogenesis, metabolism, protein content maintenance and transport. While the mitochondrial roles of PPTC7 are well-characterized, its roles outside the mitochondria are unclear. Here we identified a non-mitochondrial role for PPTC7 in regulating epidermal growth factor receptor (EGFR) trafficking. PPTC7 interacts with and dephosphorylates VPS4A, a critical ESCRT and multivesicular body-associated protein. PPTC7-mediated dephosphorylation of VPS4A at Serine 335 is required for VPS4A stability and its early endosomal localization. Either loss of PPTC7 or presence of constitutively phosphorylated VPS4A leads to defective recycling of EGFR, thus leading to EGFR re-routing to lysosomes for degradation. Further, we demonstrate that PPTC7-VPS4A-dependent EGFR recycling promotes the AKT signaling pathway thus enhancing cell proliferation and migration. Overall, our studies unveil an important mechanism where the PPTC7-VPS4A complex orchestrates an endosomal switch to promote EGFR recycling.
    Keywords:  EGFR; Endosome; Mitogen signaling; PPTC7; Receptor recycling; VPS4A
    DOI:  https://doi.org/10.1242/jcs.263676
  10. Nature. 2025 Jan;637(8045): E11-E14
    Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation.
    Max L Valenstein, Pranav V Lalgudi, Jibril F Kedir, Kendall J Condon, Anna Platzek, Daniel G Freund, Martin S Taylor, Yunhan Xu, Raghu R Chivukula, David M Sabatini.
      
    DOI:  https://doi.org/10.1038/s41586-024-07974-0
  11. EMBO J. 2025 Jan 06.
    RHEB neddylation by the UBE2F-SAG axis enhances mTORC1 activity and aggravates liver tumorigenesis.
    Fengwu Zhang, Xiufang Xiong, Zhijian Li, Haibo Wang, Weilin Wang, Yongchao Zhao, Yi Sun.
      Small GTPase RHEB is a well-known mTORC1 activator, whereas neddylation modifies cullins and non-cullin substrates to regulate their activity, subcellular localization and stability. Whether and how RHEB is subjected to neddylation modification remains unknown. Here, we report that RHEB is a substrate of NEDD8-conjugating E2 enzyme UBE2F. In cell culture, UBE2F depletion inactivates mTORC1, inhibiting cell cycle progression, cell growth and inducing autophagy. Mechanistically, UBE2F cooperates with E3 ligase SAG in neddylation of RHEB at K169 to enhance its lysosome localization and GTP-binding affinity. Furthermore, liver-specific Ube2f knockout attenuates steatosis and tumorigenesis induced by Pten loss in an mTORC1-dependent manner, suggesting a causal role of UBE2F in liver tumorigenesis. Finally, UBE2F expression levels and mTORC1 activity correlate with patient survival in hepatocellular carcinoma. Collectively, our study identifies RHEB as neddylation substrate of the UBE2F-SAG axis, and highlights the UBE2F-SAG axis as a potential target for the treatment of non-alcoholic fatty liver disease and hepatocellular carcinoma.
    Keywords:  Liver Steatosis and Tumorigenesis; Neddylation; RHEB; UBE2F; mTORC1
    DOI:  https://doi.org/10.1038/s44318-024-00353-5
  12. Proc Natl Acad Sci U S A. 2025 Jan 07. 122(1): e2413519121
    Mechanism-guided engineering of a minimal biological particle for genome editing.
    Wayne Ngo, Julia Peukes, Alisha Baldwin, Zhiwei Wayne Xue, Sidney Hwang, Robert R Stickels, Zhi Lin, Ansuman T Satpathy, James A Wells, Randy Schekman, Eva Nogales, Jennifer A Doudna.
      The widespread application of genome editing to treat and cure disease requires the delivery of genome editors into the nucleus of target cells. Enveloped delivery vehicles (EDVs) are engineered virally derived particles capable of packaging and delivering CRISPR-Cas9 ribonucleoproteins (RNPs). However, the presence of lentiviral genome encapsulation and replication proteins in EDVs has obscured the underlying delivery mechanism and precluded particle optimization. Here, we show that Cas9 RNP nuclear delivery is independent of the native lentiviral capsid structure. Instead, EDV-mediated genome editing activity corresponds directly to the number of nuclear localization sequences on the Cas9 enzyme. EDV structural analysis using cryo-electron tomography and small molecule inhibitors guided the removal of ~80% of viral residues, creating a minimal EDV (miniEDV) that retains full RNP delivery capability. MiniEDVs are 25% smaller yet package equivalent amounts of Cas9 RNPs relative to the original EDVs and demonstrated increased editing in cell lines and therapeutically relevant primary human T cells. These results show that virally derived particles can be streamlined to create efficacious genome editing delivery vehicles with simpler production and manufacturing.
    Keywords:  delivery; genome editing; viral-like particles
    DOI:  https://doi.org/10.1073/pnas.2413519121
  13. bioRxiv. 2024 Dec 23. pii: 2024.12.22.629992. [Epub ahead of print]
    A signaling inspired synthetic toolkit for efficient production of tyrosine phosphorylated proteins.
    Margaret M Ryan, Reagan Portelance, Graham F Newman, Gabrielle Martinez, Swathi Shekharan, Anqi Wu, Savannah Angel, Katherine E Schaberg, Petra Gilmore, Robert Sprung, Reid Townsend, Kristen M Naegle.
      Tyrosine phosphorylation is an important post-translational modification that regulates many biochemical signaling networks in multicellular organisms. To date, 46,000 tyrosines have been observed in human proteins, but relatively little is known about the function and regulation of most of these sites. A major challenge has been producing recombinant phospho-proteins in order to test the effects of phosphorylation. Mutagenesis to acidic amino acids often fails to replicate the size and charge of a phosphorylated tyrosine residue and synthetic amino acid incorporation has high cost with relatively low yield. Here, we demonstrate an approach, inspired by how native tyrosine kinases find targets in cells - through a secondary targeting interaction, augmenting innate catalytic specificity of a tyrosine kinase, without overriding it. We engineered complementary vector systems for multiple approaches to producing high yields of phosphoprotein products in E. coli. Here, we test phosphorylation as a function of the targeting interaction (an SH3-polyproline sequence) affinity, different reaction methods across kinases of different specificity. This system presents an inexpensive and tractable system to producing phosphoproteins and phosphopeptides and we demonstrate how it can be used for testing antibody specificity on targets of EGFR and PD-1. This methodology is a generalizable approach for enhancing the enzymatic action on a recombinant protein via the flexibility of in vitro reactions and co-expression approaches. We refer to this as SISA-KiT, for Signaling Inspired Synthetically Augmented Kinase Toolkit.
    DOI:  https://doi.org/10.1101/2024.12.22.629992
  14. bioRxiv. 2024 Dec 16. pii: 2024.12.10.627834. [Epub ahead of print]
    MatriCom: a scRNA-Seq data mining tool to infer ECM-ECM and cell-ECM communication systems.
    Rijuta Lamba, Asia M Paguntalan, Petar B Petrov, Alexandra Naba, Valerio Izzi.
      The ECM is a complex and dynamic meshwork of proteins that forms the framework of all multicellular organisms. Protein interactions within the ECM are critical to building and remodeling the ECM meshwork, while interactions between ECM proteins and cell surface receptors are essential for the initiation of signal transduction and the orchestration of cellular behaviors. Here, we report the development of MatriCom, a web application ( https://matrinet.shinyapps.io/matricom ) and a companion R package ( https://github.com/Izzilab/MatriCom ), devised to mine scRNA-Seq datasets and infer communications between ECM components and between different cell populations and the ECM. To impute interactions from expression data, MatriCom relies on a unique database, MatriComDB, that includes over 25,000 curated interactions involving matrisome components, with data on 80% of the ∼1,000 genes that compose the mammalian matrisome. MatriCom offers the option to query open-access datasets sourced from large sequencing efforts (Tabula Sapiens, The Human Protein Atlas, HuBMAP) or to process user-generated datasets. MatriCom is also tailored to account for the specific rules governing ECM protein interactions and offers options to customize the output through stringency filters. We illustrate the usability of MatriCom with the example of the human kidney matrisome communication network. Last, we demonstrate how the integration of 46 scRNA-Seq datasets led to the identification of both ubiquitous and tissue-specific ECM communication patterns. We envision that MatriCom will become a powerful resource to elucidate the roles of different cell populations in ECM-ECM and cell-ECM interactions and their dysregulations in the context of diseases such as cancer or fibrosis.
    ONE SENTENCE SUMMARY: MatriCom is a web application devised to mine scRNA sequencing datasets to infer ECM-ECM and cell-ECM communication systems in the context of the diverse cell populations that constitute any tissue or organ.
    DOI:  https://doi.org/10.1101/2024.12.10.627834
  15. Trends Cell Biol. 2025 Jan 06. pii: S0962-8924(24)00258-7. [Epub ahead of print]
    Innate versus adoptive competence: the controlled distribution of signalling receptors extends the concept of competence.
    Jessica L Bamsey, Lucy Brunt, Steffen Scholpp.
      Cellular communication through the dissemination of signal molecules is vital for tissue organisation and homeostasis. The mechanisms of signal spreading can include binding-protein-assisted transport, long membrane protrusions known as cytonemes, and exovesicles. Recent research indicates that cytonemes and exovesicles can not only transport ligands but also facilitate the regulated distribution of receptors, thereby enabling signal transduction in cells lacking endogenous receptors. This mechanism allows non-responsive cells to temporarily acquire the ability to respond to specific ligands. This review explores our understanding of ligand and receptor dispersal, offering fresh insights into the fundamental concept of cellular competence. Notably, these findings may have significant implications for diseases and their associated therapeutic targets, highlighting the urgency and importance of this research area.
    Keywords:  Wnt; competence; cytonemes; exovesicles; morphogen; receptor
    DOI:  https://doi.org/10.1016/j.tcb.2024.12.005
  16. Gigascience. 2025 Jan 06. pii: giae107. [Epub ahead of print]14
    Galaxy as a gateway to bioinformatics: Multi-Interface Galaxy Hands-on Training Suite (MIGHTS) for scRNA-seq.
    Camila L Goclowski, Julia Jakiela, Tyler Collins, Saskia Hiltemann, Morgan Howells, Marisa Loach, Jonathan Manning, Pablo Moreno, Alex Ostrovsky, Helena Rasche, Mehmet Tekman, Graeme Tyson, Pavankumar Videm, Wendi Bacon.
       BACKGROUND: Bioinformatics is fundamental to biomedical sciences, but its mastery presents a steep learning curve for bench biologists and clinicians. Learning to code while analyzing data is difficult. The curve may be flattened by separating these two aspects and providing intermediate steps for budding bioinformaticians. Single-cell analysis is in great demand from biologists and biomedical scientists, as evidenced by the proliferation of training events, materials, and collaborative global efforts like the Human Cell Atlas. However, iterative analyses lacking reinstantiation, coupled with unstandardized pipelines, have made effective single-cell training a moving target.
    FINDINGS: To address these challenges, we present a Multi-Interface Galaxy Hands-on Training Suite (MIGHTS) for single-cell RNA sequencing (scRNA-seq) analysis, which offers parallel analytical methods using a graphical interface (buttons) or code. With clear, interoperable materials, MIGHTS facilitates smooth transitions between environments. Bridging the biologist-programmer gap, MIGHTS emphasizes interdisciplinary communication for effective learning at all levels. Real-world data analysis in MIGHTS promotes critical thinking and best practices, while FAIR data principles ensure validation of results. MIGHTS is freely available, hosted on the Galaxy Training Network, and leverages Galaxy interfaces for analyses in both settings. Given the ongoing popularity of Python-based (Scanpy) and R-based (Seurat & Monocle) scRNA-seq analyses, MIGHTS enables analyses using both.
    CONCLUSIONS: MIGHTS consists of 11 tutorials, including recordings, slide decks, and interactive visualizations, and a demonstrated track record of sustainability via regular updates and community collaborations. Parallel pathways in MIGHTS enable concurrent training of scientists at any programming level, addressing the heterogeneous needs of novice bioinformaticians.
    Keywords:  Galaxy project; STEM education; bioinformatics; reproducibility; scRNA-seq; single-cell RNA-seq analysis; sustainability; training
    DOI:  https://doi.org/10.1093/gigascience/giae107
  17. Commun Biol. 2025 Jan 08. 8(1): 21
    Endothelial tip-cell position, filopodia formation and biomechanics require BMPR2 expression and signaling.
    Christian Hiepen, Mounir Benamar, Jorge Barrasa-Fano, Mar Condor, Mustafa Ilhan, Juliane Münch, Nurcan Hastar, Yannic Kerkhoff, Gregory S Harms, Thorsten Mielke, Benjamin Koenig, Stephan Block, Oliver Rocks, Salim Abdelilah-Seyfried, Hans Van Oosterwyck, Petra Knaus.
      Blood vessel formation relies on biochemical and mechanical signals, particularly during sprouting angiogenesis when endothelial tip cells (TCs) guide sprouting through filopodia formation. The contribution of BMP receptors in defining tip-cell characteristics is poorly understood. Our study combines genetic, biochemical, and molecular methods together with 3D traction force microscopy, which reveals an essential role of BMPR2 for actin-driven filopodia formation and mechanical properties of endothelial cells (ECs). Targeting of Bmpr2 reduced sprouting angiogenesis in zebrafish and BMPR2-deficient human ECs formed fewer filopodia, affecting cell migration and actomyosin localization. Spheroid assays revealed a reduced sprouting of BMPR2-deficient ECs in fibrin gels. Even more strikingly, in mosaic spheroids, BMPR2-deficient ECs failed to acquire tip-cell positions. Yet, 3D traction force microscopy revealed that these distinct cell behaviors of BMPR2-deficient tip cells cannot be explained by differences in force-induced matrix deformations, even though these cells adopted distinct cone-shaped morphologies. Notably, BMPR2 positively regulates local CDC42 activity at the plasma membrane to promote filopodia formation. Our findings reveal that BMPR2 functions as a nexus integrating biochemical and biomechanical processes crucial for TCs during angiogenesis.
    DOI:  https://doi.org/10.1038/s42003-024-07431-8
  18. Cell Chem Biol. 2024 Dec 24. pii: S2451-9456(24)00489-6. [Epub ahead of print]
    The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells.
    Gernot Wolf, Conner Craigon, Shao Thing Teoh, Patrick Essletzbichler, Svenja Onstein, Diane Cassidy, Esther C H Uijttewaal, Vojtech Dvorak, Yuting Cao, Ariel Bensimon, Ulrich Elling, Alessio Ciulli, Giulio Superti-Furga.
      Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. This approach allows scope for targeting "undruggable" proteins, and several PROTACs have reached the stage of clinical candidates. However, the roles of cellular transmembrane transporters in PROTAC uptake and efflux remain underexplored. Here, we utilized transporter-focused genetic screens to identify the ATP-binding cassette transporter ABCC1/MRP1 as a key PROTAC resistance factor. Unlike the previously identified inducible PROTAC exporter ABCB1/MDR1, ABCC1 is highly expressed among cancers of various origins and constitutively restricts PROTAC bioavailability. Moreover, in a genome-wide PROTAC resistance screen, we identified candidates involved in processes such as ubiquitination, mTOR signaling, and apoptosis as genetic factors involved in PROTAC resistance. In summary, our findings reveal ABCC1 as a crucial constitutively active efflux pump limiting PROTAC efficacy in various cancer cells, offering insights for overcoming drug resistance.
    Keywords:  ABCC1; CRISPR/Cas9; MRP1; PROTACs; drug transport; genetic screening; solute carriers (SLCs)
    DOI:  https://doi.org/10.1016/j.chembiol.2024.11.009
  19. Nat Genet. 2025 Jan 08.
    Transcript-specific enrichment enables profiling of rare cell states via single-cell RNA sequencing.
    Tsion Abay, Robert R Stickels, Meril T Takizawa, Benan N Nalbant, Yu-Hsin Hsieh, Sidney Hwang, Catherine Snopkowski, Kenny Kwok Hei Yu, Zaki Abou-Mrad, Viviane Tabar, Brooke E Howitt, Leif S Ludwig, Ronan Chaligné, Ansuman T Satpathy, Caleb A Lareau.
      Single-cell genomics technologies have accelerated our understanding of cell-state heterogeneity in diverse contexts. Although single-cell RNA sequencing identifies rare populations that express specific marker transcript combinations, traditional flow sorting requires cell surface markers with high-fidelity antibodies, limiting our ability to interrogate these populations. In addition, many single-cell studies require the isolation of nuclei from tissue, eliminating the ability to enrich learned rare cell states based on extranuclear protein markers. In the present report, we addressed these limitations by developing Programmable Enrichment via RNA FlowFISH by sequencing (PERFF-seq), a scalable assay that enables scRNA-seq profiling of subpopulations defined by the abundance of specific RNA transcripts. Across immune populations (n = 184,126 cells) and fresh-frozen and formalin-fixed, paraffin-embedded brain tissue (n = 33,145 nuclei), we demonstrated that programmable sorting logic via RNA-based cytometry can isolate rare cell populations and uncover phenotypic heterogeneity via downstream, high-throughput, single-cell genomics analyses.
    DOI:  https://doi.org/10.1038/s41588-024-02036-7
  20. Sci Adv. 2025 Jan 10. 11(2): eadp3789
    Perivascular cells function as key mediators of mechanical and structural changes in vascular capillaries.
    Cristiane M Franca, Maria Elisa Lima Verde, Alice Correa Silva-Sousa, Amin Mansoorifar, Avathamsa Athirasala, Ramesh Subbiah, Anthony Tahayeri, Mauricio Sousa, May Anny Fraga, Rahul M Visalakshan, Aaron Doe, Keith Beadle, McKenna Finley, Emilios Dimitriadis, Jennifer Bays, Marina Uroz, Kenneth M Yamada, Christopher Chen, Luiz E Bertassoni.
      A hallmark of chronic and inflammatory diseases is the formation of a fibrotic and stiff extracellular matrix (ECM), typically associated with abnormal, leaky microvascular capillaries. Mechanisms explaining how the microvasculature responds to ECM alterations remain unknown. Here, we used a microphysiological model of capillaries on a chip mimicking the characteristics of healthy or fibrotic collagen to test the hypothesis that perivascular cells mediate the response of vascular capillaries to mechanical and structural changes in the human ECM. Capillaries engineered in altered fibrotic collagen had abnormal migration of perivascular cells, reduced pericyte differentiation, increased leakage, and higher regulation of inflammatory/remodeling genes, all regulated via NOTCH3, a known mediator of endothelial-perivascular cell communication. Capillaries engineered either with endothelial cells alone or with perivascular cells silenced for NOTCH3 expression showed a minimal response to ECM alterations. These findings reveal a previously unknown mechanism of vascular response to changes in the ECM in health and disease.
    DOI:  https://doi.org/10.1126/sciadv.adp3789
  21. Nat Cardiovasc Res. 2025 Jan 08.
    Phosphorylation of endothelial histone H3.3 serine 31 by PKN1 links flow-induced signaling to proatherogenic gene expression.
    Young-June Jin, Guozheng Liang, Rui Li, ShengPeng Wang, Mohamad Wessam Alnouri, Mette Bentsen, Carsten Kuenne, Stefan Günther, Yang Yan, Yongxin Li, Nina Wettschureck, Stefan Offermanns.
      Atherosclerotic lesions develop preferentially in arterial regions exposed to disturbed blood flow, where endothelial cells acquire an inflammatory phenotype. How disturbed flow induces endothelial cell inflammation is incompletely understood. Here we show that histone H3.3 phosphorylation at serine 31 (H3.3S31) regulates disturbed-flow-induced endothelial inflammation by allowing rapid induction of FOS and FOSB, required for inflammatory gene expression. We identified protein kinase N1 (PKN1) as the kinase responsible for disturbed-flow-induced H3.3S31 phosphorylation. Disturbed flow activates PKN1 in an integrin α5β1-dependent manner and induces its translocation into the nucleus, and PKN1 is also involved in the phosphorylation of the AP-1 transcription factor JUN. Mice with endothelium-specific PKN1 loss or endothelial expression of S31 phosphorylation-deficient H.3.3 mutants show reduced endothelial inflammation and disturbed-flow-induced vascular remodeling in vitro and in vivo. Together, we identified a pathway whereby disturbed flow through PKN1-mediated histone phosphorylation and FOS/FOSB induction promotes inflammatory gene expression and vascular inflammation.
    DOI:  https://doi.org/10.1038/s44161-024-00593-y
  22. Sci Rep. 2025 Jan 08. 15(1): 649
    Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats.
    Yuka Toyoshima, Katsuyuki Nakamura, Yusuke Taguchi, Reiko Tokita, Shiho Takeuchi, Hayato Osawa, Naomi Teramoto, Hidetoshi Sugihara, Fumiaki Yoshizawa, Keitaro Yamanouchi, Shiro Minami.
      Insulin receptor substrate (IRS)-1 and IRS-2 are major molecules that transduce signals from insulin and insulin-like growth factor-I receptors. The physiological functions of these proteins have been intensively investigated in mice, while little is known in other animals. Our previous study showed that the disruption of IRS-2 impairs body growth but not glucose tolerance or insulin sensitivity in rats, which led us to hypothesize that IRS-1 plays more pivotal roles in insulin functions than IRS-2. Here, we created IRS-1 knockout (KO) rats to elucidate the physiological roles of IRS-1 in rats. The body weight of IRS-1 KO rats at birth was lower than that of wild-type (WT) littermates, and postnatal growth of IRS-1 KO rats was severely impaired. Compared with WT rats, IRS-1 KO rats displayed insulin resistance but maintained euglycemia because of compensatory hyperinsulinemia. In addition, despite the increased activity of insulin-stimulated IRS-2-associated phosphatidylinositol-3 kinase (PI3K), insulin-induced phosphorylation of the kinases downstream of PI3K was suppressed in the liver and skeletal muscle of IRS-1 KO rats. Taken together, these results indicate that in rats, IRS-1 is essential for normal growth and the glucose-lowering effects of insulin. IRS-1 appears to be more important than IRS-2 for insulin functions in rats.
    DOI:  https://doi.org/10.1038/s41598-024-84234-1
  23. Biophys J. 2025 Jan 02. pii: S0006-3495(24)04108-0. [Epub ahead of print]
    Hypo-osmotic stress shifts transcription of circadian genes.
    Androniqi Qifti, Ayobami Adeeko, Madison Rennie, Elizabeth McGlaughlin, David McKinnon, Barbara Rosati, Suzanne Scarlata.
      Cells respond to hypo-osmotic stress by initial swelling followed by intracellular increases in the number of osmolytes and initiation of gene transcription that allow cells to adapt to the stress. Here, we have studied the genes that change expression under mild hypo-osmotic stress for 12 and 24 hours in rat cultured smooth muscle cells (WKO-3M22). We find shifts in the transcription of many genes, several of which are associated with circadian rhythm, such as per1, nr1d1, per2, dbp, and Ciart. To determine whether there is a connection between osmotic stress and circadian rhythm, we first subjected cells to hypo-osmotic stress for 12 hours, and find that Bmal1, a transcription factor whose nuclear localization promotes transit through the cell cycle, localizes to the cytoplasm, which may connect osmotic stress to cell cycle. Bmal1 nuclear localization recovers after 24 hours and cell cycle resumes even though the osmotic stress remains elevated. We hypothesized that osmotic force is transmitted into the cell by deforming caveolae membrane domains releasing one of its structural proteins, cavin-1, which can travel to the nucleus and affect gene transcription. In support of this idea, we find that Bmal1 localization becomes independent of osmotic stress with cavin-1 down-regulation, and Bmal1 localization is independent of osmotic stress in a cell line with low caveolae expression. These studies indicate that osmotic stress transiently arrests circadian rhythm and cell cycle progression through caveolae deformation.
    DOI:  https://doi.org/10.1016/j.bpj.2024.12.027
  24. J Proteome Res. 2025 Jan 08.
    PTMVision: An Interactive Visualization Webserver for Post-translational Modifications of Proteins.
    Simon Hackl, Caroline Jachmann, Mathias Witte Paz, Theresa Anisja Harbig, Lennart Martens, Kay Nieselt.
      Recent improvements in methods and instruments used in mass spectrometry have greatly enhanced the detection of protein post-translational modifications (PTMs). On the computational side, the adoption of open modification search strategies now allows for the identification of a wide variety of PTMs, potentially revealing hundreds to thousands of distinct modifications in biological samples. While the observable part of the proteome is continuously growing, the visualization and interpretation of this vast amount of data in a comprehensive fashion is not yet possible. There is a clear need for methods to easily investigate the PTM landscape and to thoroughly examine modifications on proteins of interest from acquired mass spectrometry data. We present PTMVision, a web server providing an intuitive and simple way to interactively explore PTMs identified in mass spectrometry-based proteomics experiments and to analyze the modification sites of proteins within relevant context. It offers a variety of tools to visualize the PTM landscape from different angles and at different levels, such as 3D structures and contact maps, UniMod classification summaries, and site specific overviews. The web server's user-friendly interface ensures accessibility across diverse scientific backgrounds. PTMVision is available at https://ptmvision-tuevis.cs.uni-tuebingen.de/.
    Keywords:  Web server; open search; post-translational modifications; visualization
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00679
  25. Science. 2025 Jan 10. 387(6730): 126
    NIH sets out to double check biomedical studies.
    Jocelyn Kaiser.
      But so far, few investigators seem interested in having their work repeated.
    DOI:  https://doi.org/10.1126/science.adv7964
  26. PLoS One. 2025 ;20(1): e0317110
    Unveiling endothelial cell border heterogeneity: VE-cadherin adherens junction stratification by deep convolutional neural networks.
    Rudmer J Postma, Susan E Fischer, Roel Bijkerk, Anton Jan van Zonneveld.
       BACKGROUND: Systemic diseases are often associated with endothelial cell (EC) dysfunction. A key function of ECs is to maintain the barrier between the blood and the interstitial space. The integrity of the endothelial cell barrier is maintained by VE-Cadherin homophilic interactions between adjacent cells. The morphology of these borders is highly dynamic and can be actively remodeled by numerous drivers in a (patho)physiologic context specific fashion.
    OBJECTIVES: High-content screening of the impact of circulatory factors on the morphology of VE-Cadherin borders in endothelial monolayers in vitro will enable the assessment of the progression of systemic vascular disease. We therefore aimed to create an image analysis pipeline, capable of automatically analyzing images from large scale screenings, both capturing all VE-cadherin phenotypes present in a sample while preserving the higher-level 2D structure. Our pipeline is aimed at creating 1D tensor representations of the VE-cadherin adherence junction structure and negate the need for normalization.
    METHOD: An image analysis pipeline, with at the center a convolution neural network was developed. The deep neural network was trained using examples of distinct VE-Cadherin morphologies from many experiments. The generalizability of the model was extensively tested in independent experiments, before further validation using ECs exposed ex vivo to plasma from patients with liver cirrhosis and proven vascular complications.
    RESULTS: Our workflow was able to detect and stratify many of the different VE-Cadherin morphologies present within the datasets and produced similar results within independent experiments, proving the generality of the model. Finally, by EC-cell border morphology profiling, our pipeline enabled the stratification of liver cirrhosis patients and associated patient-specific morphological cell border changes to responses elicited by known inflammatory factors.
    CONCLUSION: We developed an image analysis pipeline, capable of intuitively and robustly stratifying all VE-Cadherin morphologies within a sample. Subsequent VE-Cadherin morphological profiles can be used to compare between stimuli, small molecule screenings, or assess disease progression.
    DOI:  https://doi.org/10.1371/journal.pone.0317110
  27. EMBO Rep. 2025 Jan 09.
    CRISPR-Enabled Autonomous Transposable Element (CREATE) for RNA-based gene editing and delivery.
    Yuxiao Wang, Ruei-Zeng Lin, Meghan Harris, Bianca Lavayen, Neha Diwanji, Bruce McCreedy, Robert Hofmeister, Daniel Getts.
      To address a wide range of genetic diseases, genome editing tools that can achieve targeted delivery of large genes without causing double-strand breaks (DSBs) or requiring DNA templates are necessary. Here, we introduce CRISPR-Enabled Autonomous Transposable Element (CREATE), a genome editing system that combines the programmability and precision of CRISPR/Cas9 with the RNA-mediated gene insertion capabilities of the human LINE-1 (L1) element. CREATE employs a modified L1 mRNA to carry a payload gene, and a Cas9 nickase to facilitate targeted editing by L1-mediated reverse transcription and integration without relying on DSBs or DNA templates. Using this system, we demonstrate programmable insertion of a 1.1 kb gene expression cassette into specific genomic loci of human cell lines and primary T cells. Mechanistic studies reveal that CREATE editing is highly specific with no observed off-target events. Together, these findings establish CREATE as a programmable, RNA-based gene delivery technology with broad therapeutic potential.
    Keywords:  CRISPR/Cas9; Gene Editing; Gene Therapy; Retrotransposon
    DOI:  https://doi.org/10.1038/s44319-024-00364-7
  28. Nat Commun. 2025 Jan 08. 16(1): 498
    YAP-driven malignant reprogramming of oral epithelial stem cells at single cell resolution.
    Farhoud Faraji, Sydney I Ramirez, Lauren M Clubb, Kuniaki Sato, Valeria Burghi, Thomas S Hoang, Adam Officer, Paola Y Anguiano Quiroz, William M G Galloway, Zbigniew Mikulski, Kate Medetgul-Ernar, Pauline Marangoni, Kyle B Jones, Yuwei Cao, Alfredo A Molinolo, Kenneth Kim, Kanako Sakaguchi, Joseph A Califano, Quinton Smith, Alon Goren, Ophir D Klein, Pablo Tamayo, J Silvio Gutkind.
      Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells at single cell resolution. Tumor initiating cells displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal invasive gene programs. YAP-mediated tumor initiating cell programs included activation of oncogenic transcriptional networks and mTOR signaling, and recruitment of myeloid cells to the invasive front contributing to tumor infiltration. Tumor initiating cell transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention.
    DOI:  https://doi.org/10.1038/s41467-024-55660-6
  29. Heliyon. 2024 Dec 15. 10(23): e40684
    Simple quantitation and spatial characterization of label free cellular images.
    Vincent C J de Boer, Xiang Zhang.
      Label-free imaging is routinely used during cell culture because of its minimal interference with intracellular biology and capability of observing cells over time. However, label-free image analysis is challenging due to the low contrast between foreground signals and background. So far various deep learning tools have been developed for label-free image analysis and their performance depends on the quality of training data. In this study, we developed a simple computational pipeline that requires no training data and is suited to run on images generated using high-content microscopy equipment. By combining classical image processing functions, Voronoi segmentation, Gaussian mixture modeling and automatic parameter optimization, our pipeline can be used for cell number quantification and spatial distribution characterization based on a single label-free image. We demonstrated the applicability of our pipeline in four morphologically distinct cell types with various cell densities. Our pipeline is implemented in R and does not require excessive computational power, providing novel opportunities for automated label-free image analysis for large-scale or repeated cell culture experiments.
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e40684
  30. bioRxiv. 2024 Dec 26. pii: 2024.12.26.630400. [Epub ahead of print]
    Ancestry-linked stromal variations impact breast epithelial cell invasion.
    Madison Schmidtmann, Victoria Elliott, James Clancy, Harikrishna Nakshatri, Crislyn D'Souza-Schorey.
      Breast cancer is a significant health challenge worldwide, and disproportionately affects women of African ancestry (AA) who experience higher mortality rates relative to other racial/ethnic groups. Several studies have pointed to biological factors that affect breast cancer outcomes. A recently discovered stromal cell population that expresses P ROCR, Z EB1 and P DGFRα (PZP cells) was found to be enriched in normal healthy breast tissue from AA donors, and only in tumor adjacent tissues from donors of European ancestry (EA). Here, we investigated the effect of PZP cells on the acquisition of tumorigenic phenotypes in AA and EA human breast epithelial cells to determine its contribution to the biological basis of outcome disparities. Using 3D cell models of tumor invasion, we find that PZP cells confer invasive capacity to epithelial cells independent of genetic ancestry, wherein cells exhibit leader-follower behaviors during extracellular matrix invasion. Enhanced epithelial invasion stems from a combination of AKT activation and fibronectin deposition by the PZP cells. Although activation of AKT in epithelial cells alone is insufficient to induce invasive behaviors, blocking AKT activation markedly reduces invasive capacity. These findings point to the germaneness of differences in breast biology and the multi-faceted roles and enrichment in PZP cells in AA breast tissue, in furthering current understanding of the molecular basis for worse prognosis for patients of African descent.
    DOI:  https://doi.org/10.1101/2024.12.26.630400
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