Recently, we described a novel intracellular pathway whereby EV‐containing late endosomes enter in the nucleoplasmic reticulum through type II nuclear envelope invaginations (NEI) and transfer EV cargoes into the nucleoplasm of recipient cells (Rappa et al., 2017). ![]() The transfer of EV contents through endosomal compartment to the endoplasmic reticulum (ER) has been proposed (Heusermann et al., 2016). ), the fusion of endocytosed EVs with late endosome membrane and/or the breakdown of the latter could result in exposure of EVs and/or their cargo to cellular cytosol (Joshi et al., 2020). Upon the cellular internalization of EVs by various endocytosis mechanisms (reviewed in Ref. This is specifically true for proteins and nucleic acids associated with EVs that shuttle to the nucleus of host cells (Santos et al., 2018). However, our knowledge about EV cargos’ subcellular/molecular sites of action in recipient cells is still fragmented. In cancer, their dysregulated secretion and altered cargoes (i.e., proteins, lipids and nucleic acids) can promote tumour growth and lead to metastasis (Abdouh et al., 2017 Hoshino et al., 2015 Peinado et al., 2012), suggesting that targeting EVs may prevent metastasis. Their role in modulation of immune responses, cell differentiation, and epithelial‐mesenchymal transition has been demonstrated. ![]() Knowing that cancer cells hijack their microenvironment and that EVs derived from them determine the pre‐metastatic niche, small‐sized inhibitors of nuclear transfer of EV cargo into host cells could find cancer therapeutic applications, particularly in combination with direct targeting of cancer cells.Įxtracellular vesicles (EVs), including exosomes, microvesicles and other types of membrane particles act as mediators of intercellular communication in tissues and organs under healthy and pathological conditions (Maas et al., 2017 Mathieu et al., 2019 Raposo & Stoorvogel, 2013). With novel, smaller chemical drugs, inhibition of the VOR complex was maintained, although the ICZ moieties responsible for antifungal activity and interference with intracellular cholesterol distribution were removed. Here, we report that the antifungal compound itraconazole (ICZ), but not its main metabolite hydroxy‐ICZ or ketoconazole, disrupts the binding of Rab7 to ORP3–VAP‐A complexes, leading to inhibition of EV‐mediated pro‐metastatic morphological changes including cell migration behaviour of colon cancer cells. Their entry therein and docking to outer nuclear membrane occur through a tripartite complex formed by the proteins VAP‐A, ORP3 and Rab7 (VOR complex). ![]() We have described that after endocytosis, EVs reach Rab7 + late endosomes and a fraction of these enter the nucleoplasmic reticulum and transport EV biomaterials to the host cell nucleoplasm. ![]() Extracellular vesicles (EVs) are mediators of intercellular communication under both healthy and pathological conditions, including the induction of pro‐metastatic traits, but it is not yet known how and where functional cargoes of EVs are delivered to their targets in host cell compartments.
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