The molecular conversations of sarcomas: exosomal non-coding RNAs in tumor's biology and their translational prospects

Abstract

Exosomes mediate cell-to-cell crosstalk involving a variety of biomolecules through an intricate signaling network. In recent years, the pivotal role of exosomes and their non-coding RNAs cargo in the development and progression of several cancer types clearly emerged. In particular, tumor bulk and its microenvironment co-evolve through cellular communications where these nanosized extracellular vesicles are among the most relevant actors. Knowledge about the cellular, and molecular mechanisms involved in these communications will pave the way for novel exosome-based delivery of therapeutic RNAs as well as innovative prognostic/diagnostic tools. Despite the valuable therapeutic potential and clinical relevance of exosomes, their role on sarcoma has been vaguely reported because the rarity and high heterogeneity of this type of cancer. Here, we dissected the scientific literature to unravel the multifaceted role of exosomal non-coding RNAs as mediator of cell-to-cell communications in the sarcoma subtypes.

Keywords: Exosomes; LncRNAs; Non-coding RNAs; Sarcomas; Tumor microenvironment; circRNA; microRNAs.

Fig. 1

Biogenesis, release, and uptake of exosomes. Exosomes originated from intraluminal vesicles (ILVs) and then included in multivesicular bodies (MVBs), can fuse with lysosomes and undergo to degradation or with the cell membrane to be released as exosomes into the extracellular space. The exosomes formation is a process mediated by the Endosomal Sorting Complex Required for Transport (ESCRT)-dependent pathway, which consists of four complexes from 0 to III. The release of exosomes is mediated by RABGTPase proteins and the soluble N-ethyl maleimide (NEM)-sensitive factor attachment protein receptor (SNARE) complex, which lead to MBVs and cell membranes fusion and exosome release. Exosomes uptake can be exploited by endocytosis, ligand-receptor interaction, or fusion with cell membrane. Generated with BioRender.com

Fig. 2

Biogenesis and functions of ncRNAs.> The biogenesis mechanisms and the main biological process perturbed by microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs) are depicted. Generated with BioRender.com

Fig. 3

Tumor microenvironment (TME) complexity depiction. Tumor-associated macrophages (TAMs) can have an M1 or M2 phenotype with opposite effects on anti-tumor immune surveillance. PD-L1, PD-L2 and VISTA can directly suppress T cell activity by recruiting regulatory T cells (T-reg). Cancer-associated fibroblasts (CAF) by secreting cytokines and resistance factors-loaded exosomes influence function of immune cells and can contribute chemotherapy and radiotherapy resistance. Myeloid-derived suppressor cells (MDSCs) have a strong immunosuppressive activity. Exosomes are also released by tumor cells self-enhancing proliferation, migration and immune escape. Generated with BioRender.com

Fig. 4

Summary of ncRNA enriched in sarcoma-derived exosomes and their function. Relevance of each ncRNA in the different sarcoma subtypes are exploited in the text below and in Table 1. Generated with BioRender.com

Fig. 5

Pathways enriched by sarcoma-derived exosomal miRNAs. (A) Enriched pathways using the genes union method of miRPath v4.0 (FDR < 0.001). (B) Pathways enriched using the pathway union method of miRPath v4.0 (FDR < 0.05). (C) Intersection analysis of pathways’ genes differentially expressed between sarcoma and the remaining tissues samples of TCGA dataset using the post-enrichment analysis of miRPath v4.0. (D) Detail of pathways sharing at least 3 differentially expressed genes (blue) targeted by exosomal miRNAs. Genes with log2FC values > |1| and interacting miRNAs > 0 were plotted