Abstract
Lung adenocarcinoma is heterogeneous and hierarchically organized, with a subpopulation of stem-like cells (CSCs) that reside at the apex of the hierarchy, in which exosomes act as important mediators by transporting specific molecules among different cell populations. Although there have been numerous studies on tumor exosomes, the constituents and functional properties of CSC-derived exosomes are still poorly characterized. Here we present a detail transcriptome and proteome atlas of the exosomes released by human lung adenocarcinoma stem-like cells (LSLCs). The transcriptome analysis indicates the specific patterns of exosomal constituents, including the fragmentation of transcripts and the low-level presence of circular RNAs, and identifies multiple exosomal-enriched mRNAs and lncRNAs. Integrative analysis of transcriptome and proteome data reveals the diverse functions of exosomal-enriched RNAs and proteins, many of which are associated with tumorigenesis. Importantly, several LSLC markers we identified are highly expressed in LSLC-derived exosomes and associate with poor survival, which may serve as promising liquid biopsy biomarkers for lung adenocarcinoma diagnosis. Our study provides a resource for the future elucidation of the functions of tumor-derived exosomes and their regulatory mechanisms in mediating lung cancer development.
Highlights
A solid tumor has been viewed as a community[1,2,3], in which cells communicate with each other and are hierarchically organized into distinct functional populations[4,5], such as cancer stem cells (CSCs) that are defined as “cancer root cells” and exhibit self-renewal and repopulation capacity[6,7,8]
We demonstrated that several RNAs and proteins that are expressed in lung adenocarcinoma stem-like cells (LSLCs) and associated with poor survival in lung cancer patients are packaged into exosomes, which present a source of liquid biopsy biomarkers in lung adenocarcinoma diagnosis and prognosis
Consistent with transcriptomic analysis, high concordances of the most highly expressed proteins between exosomes and their parental cells were observed (Fig. 5d); the weakly expressed proteins exhibited similar patterns to random selections. These results suggested that the transcripts or proteins that are highly expressed in LSLCs or in lung adenocarcinoma bulk cells (LBCs) were more prone to be highly expressed in their derived exosomes
Summary
A solid tumor has been viewed as a community[1,2,3], in which cells communicate with each other and are hierarchically organized into distinct functional populations[4,5], such as cancer stem cells (CSCs) that are defined as “cancer root cells” and exhibit self-renewal and repopulation capacity[6,7,8]. Intercellular communications via molecular transfer, either between CSCs and resident tumor cells or between tumor cells and their microenvironments, are key determinants of cancer development and metastasis[9,10,11]. Several intercellular communicators have been identified such as microvesicles, exosomes, and non-vesicular carriers[12,13,14]. Exosomes are endosome-derived nanovesicles (40–150 nm) secreted by most cell types and released into the extracellular space[15]. Exosomes secreted by cancer cells contain both coding and non-coding RNAs, as well as proteins, which can influence the formation and homeostasis of a tumor niche and microenvironment[12,16]. The detail characterization and functional interpretation of exosomes secreted by CSCs at both the transcriptomic and proteomic levels have not been sufficiently addressed to date
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