Exosomes from Nischarin-Expressing Cells Reduce Breast Cancer Cell Motility and Tumor Growth

Abstract

Exosomes are small extracellular microvesicles that are secreted by cells when intracellular multivesicular bodies fuse with the plasma membrane. We have previously demonstrated that Nischarin inhibits focal adhesion formation, cell migration, and invasion, leading to reduced activation of focal adhesion kinase. In this study, we propose that the tumor suppressor Nischarin regulates the release of exosomes. When cocultured on exosomes from Nischarin-positive cells, breast cancer cells exhibited reduced survival, migration, adhesion, and spreading. The same cocultures formed xenograft tumors of significantly reduced volume following injection into mice. Exosomes secreted by Nischarin-expressing tumors inhibited tumor growth. Expression of only one allele of Nischarin increased secretion of exosomes, and Rab14 activity modulated exosome secretions and cell growth. Taken together, this study reveals a novel role for Nischarin in preventing cancer cell motility, which contributes to our understanding of exosome biology. Significance: Regulation of Nischarin-mediated exosome secretion by Rab14 seems to play an important role in controlling tumor growth and migration. See related commentary by McAndrews and Kalluri, p. 2099

Knockout model reveals the role of Nischarin in mammary gland development, breast tumorigenesis and response to metformin treatment

“…These data suggest that Nischarin ablation promotes breast cancer initiation. Consistent with this, we showed that exosomes prepared from Nischarin ablated tissues promote breast tumor growth …”

“…Consistent with this, we showed that exosomes prepared from Nischarin ablated tissues promote breast tumor growth. 37 To examine the effect of Nischarin ablation on mammary cancer progression, breast tumor growth in Nc −/− -PyMT and Nc +/+ -PyMT was measured every 3 days after tumor onset. The change in tumor volume (and tumor burden) was significantly higher in Nc −/− -PyMT tumors compared to WT tumors.…”

Isoginkgetin derivative IP2 enhances the adaptive immune response against tumor antigens

“…The exon-derived TL9 epitope from the tumor suppressor nischarin was shown to be immunogenic and to synergize with IP2 in cancer vaccines to inhibit the growth of MCA205 fibrosarcoma. Recent studies highlighted the role of nischarin in the regulation of breast tumorigenesis 56 related to the secretion of exosomes from breast cancer cells 57 . The nischarin-derived TL9 epitope has been identified throughout multiple proteomic studies referenced in the Immune Epitope Database (IEDB) but has never been further exploited so far.…”

RAB5A is associated with genes involved in exosome secretion: Integration of bioinformatics analysis and experimental validation

“…In this way, using high‐throughput data via bioinformatics methods, followed by an experimental validation, is accounted as a promising and effectual strategy to discover new pathways for specific diseases or cellular mechanisms 51 . Regarding the effect of Rab GTPases family on exosomes biogenesis on the one hand 44,52,53 and the pivotal role of RAB5A (a member of Rab GTPases family) in endocytosis 8 and the endosomal origin of the exosomes 9 on the other, we reasoned that RAB5A might interact with exosome secretion‐related genes. Despite the comprehensive knowledge about RAB5A function in the endocytosis process, 7 its effect on exosome secretion is not fully understood.…”