Tumor-Derived Extracellular Vesicles: Multifunctional Entities in the Tumor Microenvironment.

Tumor cells release extracellular vesicles (EVs) that can function as mediators of intercellular communication in the tumor microenvironment. EVs contain a host of bioactive cargo, including membrane, cytosolic, and nuclear proteins, in addition to noncoding RNAs, other RNA types, and double-stranded DNA fragments. These shed vesicles may deposit paracrine information and can also be taken up by stromal cells, causing the recipient cells to undergo phenotypic changes that profoundly impact diverse facets of cancer progression.

Recruitment of DNA to tumor-derived microvesicles.

The shedding of extracellular vesicles (EVs) represents an important but understudied means of cell-cell communication in cancer. Among the currently described classes of EVs, tumor-derived microvesicles (TMVs) comprise a class of vesicles released directly from the cell surface. TMVs contain abundant cargo, including functional proteins and miRNA, which can be transferred to and alter the behavior of recipient cells.

Profiling and promise of supermeres.

Extracellular vesicles and particles have important roles in physiology and disease. Advances in isolation and characterization technologies have enabled the identification of new particles. Supermeres are the newest addition to the rapidly expanding repertoire of the cell secretome, and provide exciting opportunities for clinical translation.

The ins and outs of microvesicles.

Microvesicles are a heterogeneous group of membrane-enclosed vesicles that are released from cells into the extracellular space by the outward budding and pinching of the plasma membrane. These vesicles are loaded with multiple selectively sorted proteins and nucleic acids. Although interest in the clinical potential of microvesicles is increasing, there is only limited understanding of different types of microvesicles and the mechanisms involved in their formation.

Breaking Bad: Extracellular Vesicles Provoke Tumorigenic Responses Under Oxygen Deprivation.

Intercellular communication is vital to tumor progression. In this issue of Developmental Cell, Bertolini et al. (2020) describe how small extracellular vesicles released from hypoxic mammary tumor cells facilitate intercellular communication, leading to alterations in mitochondrial dynamics and acquisition of invasive phenotypes in normal epithelial cells.

Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth.

Breast cancer brain metastases (BCBM) have a 5-20 year latency and account for 30% of mortality; however, mechanisms governing adaptation to the brain microenvironment remain poorly defined. We combine time-course RNA-sequencing of BCBM development with a Drosophila melanogaster genetic screen, and identify Rab11b as a functional mediator of metastatic adaptation. Proteomic analysis reveals that Rab11b controls the cell surface proteome, recycling proteins required for successful interaction with the microenvironment, including integrin β1.

An ARF6-Exportin-5 axis delivers pre-miRNA cargo to tumour microvesicles.

Tumour-derived microvesicles (TMVs) comprise a class of extracellular vesicles released from tumour cells that are now understood to facilitate communication between the tumour and the surrounding microenvironment. Despite their significance, the regulatory mechanisms governing the trafficking of bioactive cargos to TMVs at the cell surface remain poorly defined. Here we describe a molecular pathway for the delivery of microRNA (miRNA) cargo to nascent TMVs involving the dissociation of a pre-miRNA/Exportin-5 complex from Ran-GTP following nuclear export and its subsequent transfer to a cytoplasmic shuttle comprised of ARF6-GTP and GRP1.

Coordinated Regulation of Intracellular Fascin Distribution Governs Tumor Microvesicle Release and Invasive Cell Capacity.

Tumor cell invasion is one result of the bidirectional interactions occurring between tumor cells and the surrounding milieu. The ability of tumor cells to invade through the extracellular matrix is in part regulated by the formation of a class of protease-loaded extracellular vesicles, called tumor microvesicles (TMVs), which are released directly from the cell surface. Here we show that the actin bundling protein, fascin, redistributes to the cell periphery in a ternary complex with podocalyxin and ezrin, where it promotes TMV release.

Aberrant endocytosis leads to the loss of normal mitotic spindle orientation during epithelial glandular morphogenesis.

Epithelial cells form tissues with many functions, including secretion and environmental separation and protection. Glandular epithelial tissues comprise cysts and tubules that are formed from a polarized, single-epithelial cell layer surrounding a central, fluid-filled lumen. The pathways regulating key processes in epithelial tissue morphogenesis such as mitotic spindle formation are incompletely understood, but are important to investigate, as their dysregulation is a signature of epithelial tumors.

Extracellular microvesicles and invadopodia mediate non-overlapping modes of tumor cell invasion.

Tumor cell invasion requires the molecular and physical adaptation of both the cell and its microenvironment. Here we show that tumor cells are able to switch between the use of microvesicles and invadopodia to facilitate invasion through the extracellular matrix. Invadopodia formation accompanies the mesenchymal mode of migration on firm matrices and is facilitated by Rac1 activation.

Tumor-derived microvesicles in the tumor microenvironment: How vesicle heterogeneity can shape the future of a rapidly expanding field.

Information transmission from tumor cells to non-tumor cells in the surrounding microenvironment via microvesicles is a more recently studied form of intercellular signaling that can have a marked impact on the tumor microenvironment. Tumor-derived microvesicles (TMVs) are packed with information including signaling proteins and nucleic acids, and can be taken up by target cells, enabling paracrine signaling. While previous research has focused on how vesicles released from pathologic cells differ from normal cells, the heterogeneity that exists within the TMV population itself is not fully characterized, and only beginning to be appreciated.

Regulated delivery of molecular cargo to invasive tumour-derived microvesicles.

Cells release multiple, distinct forms of extracellular vesicles including structures known as microvesicles, which are known to alter the extracellular environment. Despite growing understanding of microvesicle biogenesis, function and contents, mechanisms regulating cargo delivery and enrichment remain largely unknown. Here we demonstrate that in amoeboid-like invasive tumour cell lines, the v-SNARE, VAMP3, regulates delivery of microvesicle cargo such as the membrane-type 1 matrix metalloprotease (MT1-MMP) to shedding microvesicles.

Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers.

Recent advances in the study of tumor-derived microvesicles reveal new insights into the cellular basis of disease progression and the potential to translate this knowledge into innovative approaches for cancer diagnostics and personalized therapy. Tumor-derived microvesicles are heterogeneous membrane-bound sacs that are shed from the surfaces of tumor cells into the extracellular environment. They have been thought to deposit paracrine information and create paths of least resistance, as well as be taken up by cells in the tumor microenvironment to modulate the molecular makeup and behavior of recipient cells.

Microvesicles: mediators of extracellular communication during cancer progression.

Microvesicles are generated by the outward budding and fission of membrane vesicles from the cell surface. Recent studies suggest that microvesicle shedding is a highly regulated process that occurs in a spectrum of cell types and, more frequently, in tumor cells. Microvesicles have been widely detected in various biological fluids including peripheral blood, urine and ascitic fluids, and their function and composition depend on the cells from which they originate.