Tumor-derived extracellular vesicles (EVs) facilitate metastatic progression by transferring bioactive cargo to recipient cells, thereby increasing endothelial permeability and promoting angiogenesis. The harsh conditions of the tumor microenvironment, such as extracellular acidosis, can alter the content of EVs, leading to changes in recipient cells, including endoplasmic reticulum (ER) stress. This study aimed to investigate whether EVs released by tumor cells adapted to acidosis or ER stress can alter endothelial functional properties. ER stress was induced in MDA-MB-231 breast cancer cells with tunicamycin, and adaptation to acidosis was achieved by culturing at pH 6.5 for 30 days. Large extracellular vesicles (LEVs) in these conditions were isolated by centrifugation. LEVs were characterized by nanoparticle tracking analysis (NTA), immunogold, Western blot, and high-performance liquid chromatography (HPLC). ER stress and autophagy markers were quantified by Western blot; cancer cells' adhesion to endothelial cells was assessed by adhesion assay; barrier permeability by dextran diffusion in an organ-on-a-chip model; migration by wound healing assay, and angiogenesis by tube formation assay. Tunicamycin was not detected in LEV from tunicamycin-treated cells (LEV T). LEV T increased the migration of endothelial cells, while not inducing ER stress, nor altering adhesion, angiogenesis, or permeability. Acidosis-adapted cells did not have greater UPR activation, but their LEVs (LEV 6.5) induced ER stress, reduced adhesion and angiogenesis, and increased permeability and migration. These findings indicate that LEVs from acidosis-adapted tumor cells reprogram endothelial physiology, supporting a potential role in metastatic progression.

Extracellular vesicles (EV) secreted by living cells are important players in cell-to-cell communication, particularly in the diffuse immune system, where they contribute to local and systemic coordination. Indeed, EV are in the ideal size range for diffusion in interstitial and lymphatic fluids, which is the main route of tissue EV trafficking towards secondary lymphoid organs that orchestrate immune responses. In the lymph nodes, EV interact with multiple immune and stromal cell populations sensitive to antigens and co-delivered tissue messages via degradative and non-degradative pathways. Natural conveyers of bioactive compounds inherited from their mother cells and their surroundings, EV modulate innate and adaptive immune responses in health and disease. The aim of this scoping review is to aggregate information from the literature on cellular effectors and molecular pathways of EV-mediated immune responses in the lymph node environment and to gain insight into practices using EV for immune intervention .

Lamin A is a major contributor to nuclear mechanics and an important mediator of mechanotransduction. While its role in regulating nuclear architecture is well established, considerably less attention has been given to how mechanical cues regulate lamin A itself. Here, we review current evidence demonstrating that lamin A homeostasis is dynamically controlled by mechanical stimulation through transcriptional, translational, and post-translational mechanisms regulating protein abundance, stability, and turnover. We further discuss emerging evidence suggesting that prelamin A maturation, a highly conserved multistep processing pathway, may represent a previously unrecognized mechanosensitive regulatory node. Recent studies challenge the canonical model of prelamin A processing and raise the possibility of alternative maturation pathways with important implications for lamin A homeostasis. We highlight current evidence, unresolved questions, and future directions, proposing that mechanical regulation of lamin A biogenesis represents an underexplored dimension of lamin mechanobiology with broad implications for development, aging, laminopathies, and mechanically driven diseases.

The mammalian vestibular system has two types of sensory receptor hair cells (HCs), each with different neurotransmission mechanisms. Type II HCs use ribbon synapses to transmit neurotransmitters like glutamate to bouton terminals of afferent neurons. Type I HCs are nearly engulfed by a calyceal afferent ending. They regulate afferent activity through both quantal and non-quantal transmission (NQT), the latter faster than classic neurotransmitter release and potentially key to stabilizing vision and balance during rapid head movements. Here, we describe a novel striated contact, present only in the mouse type I HC and its calyceal afferent ending. Electron tomography reveals periodic striations on both the HC and calyx plasma membranes. These contact sites are intimately associated with a plasma membrane mitochondria contact site on the type I HC side of the synapse. Given that mitochondrion-plasma membrane contact sites in other systems regulate local ion homeostasis, this distinctive arrangement has the potential to serve or modulate NQT at the type I HC-calyx synapse.

Manumycin A (MA) is a natural antibiotic produced by Streptomyces parvulus, originally reported as a selective Ras farnesyltransferase inhibitor. Over the years, it has been established as a valuable agent in the studies of the molecular biology of cancer. Recent interest in the use of MA as an inhibitor of extracellular vesicles (EV) shows new perspectives for this small molecule in view of the urgent need for effective molecular tools for this application. This review summarizes the current knowledge on Manumycin A, with a particular focus on its potential utility in EV-related biomedical studies. The inhibitory mechanism and possible application limitations are discussed, and current results of studies involving MA have been presented. Conclusions include remarks that the actual cellular response can vary depending on cell type and dose, and due to the risk of cytotoxic effects, MA requires a cautious approach. Although available data indicate that Manumycin A may be considered to be used as an inhibitor of extracellular vesicles, the exact mechanism of action still requires further comprehensive investigation. Therefore, it would be desirable for any study that uses Manumycin A as an inhibitor to also include a thorough characterization of the effect of the dose on cells and extracellular vesicles using various research techniques.

Gut homeostasis relies on the tightly controlled balance between intestinal stem cell self-renewal and differentiation. The clathrin adaptor complex AP-1B plays a pivotal role in establishing the polarity of enterocytes as well as in the asymmetric distribution of membrane proteins, including the brush border transporters that govern intestinal absorption. Additionally, AP-1B has been involved in the control of intestinal cell proliferation, which suggests that it may regulate various aspects of gut functional organisation. In this study, we investigated the consequences of conditional mutations of the gene encoding the AP-1B subunit μ1B (Ap1m2) in mouse enteroids. We first showed in this model that Ap1m2 mutations also induce strong polarity defects at the subcellular level in the absorptive enterocytes. Next, we unveiled that AP-1B regulates intestinal cell differentiation at the tissular level, through the commitment of stem/progenitor cells towards the secretory lineage and cell positioning along the crypt-villus axis. Furthermore, we showed that AP-1B inhibition also induces hyperproliferation in enteroids. Notably, we unravelled that, complementary to the Wnt/β-catenin-mediated proliferation described in null mice, AP-1B downregulation triggers a tissue-autonomous, mTOR/YAP-dependent, proliferative pathway. Overall, these results enlighten the pleiotropic roles played by AP-1B in the homeostasis of the gut epithelium.

Colorectal cancer (CRC) develops through the stepwise accumulation of genetic alterations, including mutations in APC, KRAS, and TP53, which drive tumor initiation and progression. Although advances in genomic profiling have significantly improved our understanding of CRC, translating these alterations into functional outcomes and therapeutic responses remains a major challenge. This limitation arises from tumor heterogeneity, context-dependent signaling, and the dynamic nature of tumor evolution. Recent advances in patient-derived organoids (PDOs) have provided a platform that preserves tumor-specific architecture and genetic features, enabling functional interrogation of drug responses. However, PDOs lack critical components of the tumor microenvironment, such as stromal, immune, and mechanical cues. Organ-on-a-chip (OoC) technologies, particularly organoid-on-a-chip systems in which PDOs are integrated into microfluidic devices, further address these limitations by recapitulating physiological conditions and multicellular interactions. In this review, we discuss the genetic evolution of CRC and highlight how emerging functional models, including PDOs and organoid-on-a-chip platforms, bridge the gap between genomic alterations and tumor behavior. We propose that integrating these platforms offers a promising framework for advancing functional precision medicine and improving our understanding of CRC biology.

Xenopus laevis survives seasonal droughts by entering a hypometabolic state known as aestivation. One of the mechanisms employed by X. laevis to mitigate aestivation-induced tissue atrophy is gene regulation of pro-survival proteins. We further expand on the role of anti-apoptotic signaling in X. laevis by investigating the effect of signal transducer and activator of transcription (STAT) signaling on downstream anti-apoptotic genes in control and dehydrated liver and skeletal muscle of X. laevis. Herein, we found that STAT signaling is differentially regulated between tissues. STAT3 signaling in the liver and STAT5 signaling in skeletal muscle lead to the selective upregulation of downstream anti-apoptotic proteins. Additionally, pro-apoptotic STAT1 signaling is found to be attenuated in both tissues during dehydration stress. Overall, our results indicate an important role for anti-apoptotic proteins during dehydration stress and their contribution in mitigating aestivation-induced atrophy.