RanGTPase links nucleo-cytoplasmic transport to the recruitment of cargoes into small extracellular vesicles.

Small extracellular vesicle (sEV)-mediated intercellular communication regulates multiple aspects of growth and development in multicellular organisms. However, the mechanism underlying cargo recruitment into sEVs is currently unclear. We show that the key nucleo-cytoplasmic transport (NCT) protein-RanGTPase, in its GTP-bound form (RanGTP), is enriched in sEVs secreted by mammalian cells. This recruitment of RanGTP into sEVs depends on the export receptor CRM1 (also called XPO1). The recruitment of GAPDH, a candidate cargo protein, into sEVs is regulated by the RanGTP-CRM1axis in a nuclear export signal (NES)-dependent manner. Perturbation of NCT through overexpression or depletion of nuclear transport components affected the recruitment of Ran, CRM1 and GAPDH into sEVs. Our studies, thus, suggest a link between NCT, particularly the Ran-CRM1 axis, and recruitment of NES-containing cargoes into the sEVs. Collectively, these findings implicate RanGTPase as a link between NCT and sEV mediated intercellular communication.

Metabostemness in cancer: Linking metaboloepigenetics and mitophagy in remodeling cancer stem cells.

Cancer stem cells (CSCs) are rare populations of malignant cells with stem cell-like features of self-renewal, uninterrupted differentiation, tumorigenicity, and resistance to conventional therapeutic agents, and these cells have a decisive role in treatment failure and tumor relapse. The self-renewal potential of CSCs with atypical activation of developmental signaling pathways involves the maintenance of stemness to support cancer progression. The acquisition of stemness in CSCs has been accomplished through genetic and epigenetic rewiring following the metabolic switch. In this context, "metabostemness" denotes the metabolic parameters that essentially govern the epitranscriptional gene reprogramming mechanism to dedifferentiate tumor cells into CSCs. Several metabolites often referred to as oncometabolites can directly remodel chromatin structure and thereby influence the operation of epitranscriptional circuits. This integrated metaboloepigenetic dimension of CSCs favors the differentiated cells to move in dedifferentiated macrostates. Some metabolic events might perform as early drivers of epitranscriptional reprogramming; however, subsequent metabolic hits may govern the retention of stemness properties in the tumor mass. Interestingly, selective removal of mitochondria through autophagy can promote metabolic plasticity and alter metabolic states during differentiation and dedifferentiation. In this connection, novel metabostemness-specific drugs can be generated as potential cancer therapeutics to target the metaboloepigenetic circuitry to eliminate CSCs.