The role of Caveolin-1 in tumor-derived extracellular vesicle biology and its implications Satish Kailasam Mani, Christophe Lamaze, Cristian Saquel Frontiers in Cell and Developmental Biology, 2025 Tumor-derived extracellular vesicles (TEVs) are increasingly recognized as key mediators of intercellular communication between cancer cells and their environment, a process crucial for tumor progression. TEVs can act locally on neighboring cells or travel long distances to impact remote tissues, thereby promoting tumor growth, cell invasion, pre-metastatic niche formation, and ultimately, metastasis. Despite significant insights into the molecular mechanisms by which TEVs shape the tumor microenvironment (TME) and induce pro-metastatic effects in recipient cells, many questions remain unanswered. Recent studies suggest that caveolae, invaginations of the plasma membrane with critical roles in cellular mechanics, may play an important role in TEV-mediated metastatic trait acquisition by cancer cells. The presence of caveolin-1 (Cav1) in EVs supports its involvement in EV dynamics, including biogenesis, secretion and uptake by recipient cells. Further research into the role of Cav1 in EV-mediated cancer progression could pave the way for improved diagnostic tools and novel therapeutic strategies in cancer treatment.
Neuronal activity-dependent ATP enhances the pro-growth effect of repair Schwann cell extracellular vesicles by increasing their miRNA-21 loading Cristian Saquel, Romina J. Catalan, Rodrigo Lopez-Leal, Ramon A. Ramirez, David Necuñir, et al. Frontiers in Cellular Neuroscience, 2022 Functional recovery after peripheral nerve injuries is critically dependent on axonal regeneration. Several autonomous and non-cell autonomous processes regulate axonal regeneration, including the activation of a growth-associated transcriptional program in neurons and the reprogramming of differentiated Schwann cells (dSCs) into repair SCs (rSCs), triggering the secretion of neurotrophic factors and the activation of an inflammatory response. Repair Schwann cells also release pro-regenerative extracellular vesicles (EVs), but is still unknown whether EV secretion is regulated non-cell autonomously by the regenerating neuron. Interestingly, it has been described that nerve activity enhances axonal regeneration by increasing the secretion of neurotrophic factors by rSC, but whether this activity modulates pro-regenerative EV secretion by rSC has not yet been explored. Here, we demonstrate that neuronal activity enhances the release of rSC-derived EVs and their transfer to neurons. This effect is mediated by activation of P2Y receptors in SCs after activity-dependent ATP release from sensory neurons. Importantly, activation of P2Y in rSCs also increases the amount of miRNA-21 present in rSC-EVs. Taken together, our results demonstrate that neuron to glia communication by ATP-P2Y signaling regulates the content of SC-derived EVs and their transfer to axons, modulating axonal elongation in a non-cell autonomous manner.
Schwann cell reprogramming into repair cells increases miRNA-21 expression in exosomes promoting axonal growth Rodrigo López-Leal, Florencia Díaz-Viraqué, Romina J. Catalán, Cristian Saquel, Anton Enright, et al. Journal of Cell Science, 2020 Functional recovery after peripheral nerve damage is dependent on the reprogramming of differentiated Schwann cells (dSCs) into repair Schwann cells (rSCs), which promotes axonal regeneration and tissue homeostasis. Transition into a repair phenotype requires expression of c-Jun and Sox2, which transcriptionally mediates inhibition of the dSC program of myelination and activates a non-cell-autonomous repair program, characterized by the secretion of neuronal survival and regenerative molecules, formation of a cellular scaffold to guide regenerating axons and activation of an innate immune response. Moreover, rSCs release exosomes that are internalized by peripheral neurons, promoting axonal regeneration. Here, we demonstrate that reprogramming of Schwann cells (SCs) is accompanied by a shift in the capacity of their secreted exosomes to promote neurite growth, which is dependent on the expression of c-Jun (also known as Jun) and Sox2 by rSCs. Furthermore, increased expression of miRNA-21 is responsible for the pro-regenerative capacity of rSC exosomes, which is associated with PTEN downregulation and PI3-kinase activation in neurons. We propose that modification of exosomal cargo constitutes another important feature of the repair program of SCs, contributing to axonal regeneration and functional recovery after nerve injury.
Axonal degeneration is mediated by necroptosis activation Macarena S. Arrázola, Cristian Saquel, Romina J. Catalán, Sebastián A. Barrientos, Diego E. Hernandez, et al. Journal of Neuroscience, 2019 Axonal degeneration, which contributes to functional impairment in several disorders of the nervous system, is an important target for neuroprotection. Several individual factors and subcellular events have been implicated in axonal degeneration, but researchers have so far been unable to identify an integrative signaling pathway activating this self-destructive process. Through pharmacological and genetic approaches, we tested whether necroptosis, a regulated cell-death mechanism implicated in the pathogenesis of several neurodegenerative diseases, is involved in axonal degeneration. Pharmacological inhibition of the necroptotic kinase RIPK1 using necrostatin-1 strongly delayed axonal degeneration in the peripheral nervous system and CNS of wild-type mice of either sex and protectedin vitrosensory axons from degeneration after mechanical and toxic insults. These effects were also observed after genetic knock-down ofRIPK3, a second key regulator of necroptosis, and the downstream effectorMLKL(Mixed Lineage Kinase Domain-Like). RIPK1 inhibition prevented mitochondrial fragmentationin vitroandin vivo, a typical feature of necrotic death, and inhibition of mitochondrial fission by Mdivi also resulted in reduced axonal loss in damaged nerves. Furthermore, electrophysiological analysis demonstrated that inhibition of necroptosis delays not only the morphological degeneration of axons, but also the loss of their electrophysiological function after nerve injury. Activation of the necroptotic pathway early during injury-induced axonal degeneration was made evident by increased phosphorylation of the downstream effector MLKL. Our results demonstrate that axonal degeneration proceeds by necroptosis, thus defining a novel mechanistic framework in the axonal degenerative cascade for therapeutic interventions in a wide variety of conditions that lead to neuronal loss and functional impairment.SIGNIFICANCE STATEMENTWe show that axonal degeneration triggered by diverse stimuli is mediated by the activation of the necroptotic programmed cell-death program by a cell-autonomous mechanism. This work represents a critical advance for the field since it identifies a defined degenerative pathway involved in axonal degeneration in both the peripheral nervous system and the CNS, a process that has been proposed as an early event in several neurodegenerative conditions and a major contributor to neuronal death. The identification of necroptosis as a key mechanism for axonal degeneration is an important step toward the development of novel therapeutic strategies for nervous-system disorders, particularly those related to chemotherapy-induced peripheral neuropathies or CNS diseases in which axonal degeneration is a common factor.
RECENT SCHOLAR PUBLICATIONS
The role of Caveolin-1 in tumor-derived extracellular vesicle biology and its implications S Kailasam Mani, C Lamaze, C Saquel Frontiers in Cell and Developmental Biology 13, 1656953 , 2025 2025 Citations: 3
Mechanical stress and caveolin-1 control the release of extracellular vesicles with increased tumorigenic properties C Saquel, L Bochler, E MacDonald, C Gracia, C Viaris de Lesegno, ... bioRxiv, 2024.09. 05.611225 , 2024 2024 Citations: 2
Neuronal activity-dependent ATP enhances the pro-growth effect of repair Schwann cell extracellular vesicles by increasing their miRNA-21 loading C Saquel, RJ Catalan, R Lopez-Leal, RA Ramirez, D Necuñir, U Wyneken, ... Frontiers in Cellular Neuroscience 16, 943506 , 2022 2022 Citations: 14
Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates P García-Huerta, P Troncoso-Escudero, D Wu, A Thiruvalluvan, ... Acta neuropathologica 140 (5), 737-764 , 2020 2020 Citations: 76
Schwann cell reprogramming into repair cells increases miRNA-21 expression in exosomes promoting axonal growth R López-Leal, F Díaz-Viraqué, RJ Catalán, C Saquel, A Enright, G Iraola, ... Journal of cell science 133 (12), jcs239004 , 2020 2020 Citations: 132
The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease M Oñate, A Catenaccio, N Salvadores, C Saquel, A Martinez, ... Cell Death & Differentiation 27 (4), 1169-1185 , 2020 2020 Citations: 142
Correction: The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease M Oñate, A Catenaccio, N Salvadores, C Saquel, A Martinez, ... Cell death and differentiation 27 (7), 2294 , 2020 2020 Citations: 4
Court, FA Schwann cell reprogramming into repair cells increases exosome-loaded miRNA-21 promoting axonal growth R Lopez-Leal, F Diaz-Viraque, RJ Catalan, C Saquel, A Enright, G Iraola J. Cell Sci 133 , 2020 2020 Citations: 5
Axonal degeneration is mediated by necroptosis activation MS Arrázola, C Saquel, RJ Catalán, SA Barrientos, DE Hernandez, ... The Journal of Neuroscience 39 (20), 3832-3844 , 2019 2019 Citations: 74
MOST CITED SCHOLAR PUBLICATIONS
The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease M Oñate, A Catenaccio, N Salvadores, C Saquel, A Martinez, ... Cell Death & Differentiation 27 (4), 1169-1185 , 2020 2020 Citations: 142
Schwann cell reprogramming into repair cells increases miRNA-21 expression in exosomes promoting axonal growth R López-Leal, F Díaz-Viraqué, RJ Catalán, C Saquel, A Enright, G Iraola, ... Journal of cell science 133 (12), jcs239004 , 2020 2020 Citations: 132
Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates P García-Huerta, P Troncoso-Escudero, D Wu, A Thiruvalluvan, ... Acta neuropathologica 140 (5), 737-764 , 2020 2020 Citations: 76
Axonal degeneration is mediated by necroptosis activation MS Arrázola, C Saquel, RJ Catalán, SA Barrientos, DE Hernandez, ... The Journal of Neuroscience 39 (20), 3832-3844 , 2019 2019 Citations: 74
Neuronal activity-dependent ATP enhances the pro-growth effect of repair Schwann cell extracellular vesicles by increasing their miRNA-21 loading C Saquel, RJ Catalan, R Lopez-Leal, RA Ramirez, D Necuñir, U Wyneken, ... Frontiers in Cellular Neuroscience 16, 943506 , 2022 2022 Citations: 14
Court, FA Schwann cell reprogramming into repair cells increases exosome-loaded miRNA-21 promoting axonal growth R Lopez-Leal, F Diaz-Viraque, RJ Catalan, C Saquel, A Enright, G Iraola J. Cell Sci 133 , 2020 2020 Citations: 5
Correction: The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease M Oñate, A Catenaccio, N Salvadores, C Saquel, A Martinez, ... Cell death and differentiation 27 (7), 2294 , 2020 2020 Citations: 4
The role of Caveolin-1 in tumor-derived extracellular vesicle biology and its implications S Kailasam Mani, C Lamaze, C Saquel Frontiers in Cell and Developmental Biology 13, 1656953 , 2025 2025 Citations: 3
Mechanical stress and caveolin-1 control the release of extracellular vesicles with increased tumorigenic properties C Saquel, L Bochler, E MacDonald, C Gracia, C Viaris de Lesegno, ... bioRxiv, 2024.09. 05.611225 , 2024 2024 Citations: 2
