Dr. Lorico’s lab is focused on the mechanisms of cell-cell communications in cancer with special emphasis on mechanisms of cell fusion and on extracellular vesicles, including their characterization, intracellular pathways, and possible use as therapeutic targets and cancer biomarkers. Dr. Lorico’s lab has recently discovered “spathasomes”, subdomains of Rab7+ late endosomes, and nuclear envelope invaginations that come together to create a sub-nuclear compartment, where biomaterials associated with extracellular vesicles are delivered.
CD9-GFP+ EV-derived Biomaterials Localized in N-ALE (spathasomes)
Cells were infected with baculovirus encoding Rab7–RFP and then incubated for 4.5 h with 5 x 107 CD9-GFP+ EVs derived from CD9-GFP+ FEMX-I cells prior to staining with SUN2 Ab and analysis by CLSM. 3D reconstructions of one cell are shown. A relevant area (yellow square) covering nuclear envelope invaginations with Rab7+ late endosomes (LE) containing CD9-GFP signals (purple, red, and yellow arrowheads, respectively) is enlarged. Scale bars, 5 µm. Figure 3, Rappa et al., Oncotarget, 2017.
Entry and Delivery of Extracellular Vesicle (EV)-Derived Cargo Molecules into the Nucleoplasm of Recipient Cells
A, Two major steps are proposed to explain the delivery of EV-associated molecules to the nuclear compartment of recipient cells. First, the EVs are internalized by endocytosis at the plasma membrane (i). Second, once inside the endocytic pathway, a fraction of late endosomes (LE) penetrates the nuclear envelope invaginations (NEI) where their content, notably the endocytosed EV-associated molecules, are transferred into the nucleoplasm (ii). B, VAP-A and ORP3 form a tripartite complex with late endosome-associated Rab7 protein and are indispensable for the entry and/or tether of late endosomes to the NEI (I). Nuclear pores are somehow involved in the translocation of EV-associated soluble (II) and membranous (III) cargo molecules into the nucleus. It remains to be explained how membranous components of EVs are extracted from the late endosomal membrane upon fusion of the former with the latter and the transport mechanism through nuclear pores, which are size restricted. C, Silencing CD9 in recipient cells and/or EVs interferes with the endocytosis of EVs and the nuclear transfer of their cargo molecules. Although the presence of divalent CD9 Ab stimulated these events with native cells and EVs, the lack of CD9 abrogated them. Figure 1, Santos et al., J Cell Mol Med, 2019.