Oxidative stress induces extracellular vesicle release by upregulation of HEXB to facilitate tumour growth in experimental hepatocellular carcinoma.

Extracellular vesicles (EVs) play a crucial role in triggering tumour-aggressive behaviours. However, the energetic process by which tumour cells produce EVs remains poorly understood. Here, we demonstrate the involvement of ß-hexosaminidase B (HEXB) in mediating EV release in response to oxidative stress, thereby promoting the development of hepatocellular carcinoma (HCC). Mechanistically, reactive oxygen species (ROS) stimulate the nuclear translocation of transcription factor EB (TFEB), leading to the upregulation of both HEXB and its antisense lncRNA HEXB-AS. HEXB-AS can bind HEXB to form a protein/RNA complex, which elevates the protein stability of HEXB. The stabilized HEXB interacts with lysosome-associated membrane glycoprotein 1 (LAMP1), disrupting lysosome-multivesicular body (MVB) fusion, which protects EVs from degradation. Knockdown of HEXB efficiently inhibits EV release and curbs HCC growth both in vitro and in vivo. Moreover, targeting HEXB by M-31850 significantly inhibits HCC growth, especially when combined with GW4869, an inhibitor of exosome release. Our results underscore the critical role of HEXB as a modulator that promotes EV release during HCC development.

Autophagy orchestrates the crosstalk between cells and organs.

Over the recent years, it has become apparent that a deeper understanding of cell-to-cell and organ-to-organ communication is necessary to fully comprehend both homeostatic and pathological states. Autophagy is indispensable for cellular development, function, and homeostasis. A crucial aspect is that autophagy can also mediate these processes through its secretory role. The autophagy-derived secretome relays its extracellular signals in the form of nutrients, proteins, mitochondria, and extracellular vesicles. These crosstalk mediators functionally shape cell fate decisions, tissue microenvironment and systemic physiology. The diversity of the secreted cargo elicits an equally diverse type of responses, which span over metabolic, inflammatory, and structural adaptations in disease and homeostasis. We review here the emerging role of the autophagy-derived secretome in the communication between different cell types and organs and discuss the mechanisms involved.

An estimate of extracellular vesicle secretion rates of human blood cells.

Extracellular vesicles (EVs) have been implicated in the intercellular transfer of RNA and proteins through cellular secretion into the extracellular space. In blood plasma, circulating EVs are mainly derived from blood cells; however, factors that control plasma EV abundance are largely unknown. Here, we estimate the EV secretion rates for blood cell types using reported values for cell-specific plasma EV abundances and their parental cell's ubiquity in healthy humans. While we found that plasma contains on average ∼2 plasma EVs/cell, the cell-specific EV-to-cell ratio spanned four orders of magnitude from 0.13 ± 0.1 erythrocyte-derived EVs/erythrocyte to (1.9 ± 1.3) × 103 monocyte-derived EVs/monocyte. The steady-state plasma EV level was maintained by an estimated plasma EV secretion rate of (1.5 ± 0.4) ×  1012 EVs/min. The cell-specific secretion rate estimates were highest for monocytes (45 ± 21 EVs/cell/min) and lowest for erythrocytes ((3.2 ± 3.0) ×  10-3 EVs/cell/min). The estimated basal cell-specific EV secretion rates were not significantly correlated to the cell's lifespan or size; however, we observed a highly significant correlation to cellular mitochondrial enzyme activities. Together, our analysis indicates that cell-specific mitochondrial metabolism, for example, via reactive oxygen species, affects plasma EV abundance through increased secretion rates, and the results provide a resource for understanding EV function in human health and disease.