Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation

Fatima Qadir,Iain L Hutchison,Dhiresh Raithatha,Mohammad Arshad Aziz,Seyedeh P Poorkasreiy,Ahmad Waseem,Haiyan Dai,Lucas Girotto Lagreca Da Silva,Chrisdina Puspita Sari,Muy-Teck Teh,Hong Ma,Xun Wang,Muhammad Hussain

doi:10.1186/s12943-018-0846-5

Abstract

BackgroundExosomes are extracellular vesicles released by almost all cell types, including cancer cells, into bodily fluids such as saliva, plasma, breast milk, semen, urine, cerebrospinal fluid, amniotic fluid, synovial fluid and sputum. Their key function being intercellular communication with both neighbouring as well as distant cells. Cancer exosomes have been shown to regulate organ-specific metastasis. However, little is known about the functional differences and molecular consequences of normal cells responding to exosomes derived from normal cells compared to those derived from cancer cells.MethodsHere, we characterised and compared the transcriptome profiles of primary human normal oral keratinocytes (HNOK) in response to exosomes isolated from either primary HNOK or head and neck squamous cell carcinoma (HNSCC) cell lines.ResultsIn recipient HNOK cells, we found that regardless of normal or cancer derived, exosomes altered molecular programmes involved in matrix modulation (MMP9), cytoskeletal remodelling (TUBB6, FEZ1, CCT6A), viral/dsRNA-induced interferon (OAS1, IFI6), anti-inflammatory (TSC22D3), deubiquitin (OTUD1), lipid metabolism and membrane trafficking (BBOX1, LRP11, RAB6A). Interestingly, cancer exosomes, but not normal exosomes, modulated expression of matrix remodelling (EFEMP1, DDK3, SPARC), cell cycle (EEF2K), membrane remodelling (LAMP2, SRPX), differentiation (SPRR2E), apoptosis (CTSC), transcription/translation (KLF6, PUS7). We have also identified CEP55 as a potential cancer exosomal marker.ConclusionsIn conclusion, both normal and cancer exosomes modulated unique gene expression pathways in normal recipient cells. Cancer cells may exploit exosomes to confer transcriptome reprogramming that leads to cancer-associated pathologies such as angiogenesis, immune evasion/modulation, cell fate alteration and metastasis. Molecular pathways and biomarkers identified in this study may be clinically exploitable for developing novel liquid-biopsy based diagnostics and immunotherapies.

Highlights

Exosomes are extracellular vesicles released by almost all cell types, including cancer cells, into bodily fluids such as saliva, plasma, breast milk, semen, urine, cerebrospinal fluid, amniotic fluid, synovial fluid and sputum
It has been suggested that tumour cells exploit this intercellular communication mechanism to confer target cell reprogramming that leads to cancer-associated pathologies such as angiogenesis, immune evasion/modulation, cell fate alteration and metastasis
Physical characterisation and verification of Exosomal proteins To confirm exosomal particle size, shape, membrane structure and particle concentrations, we have used a number of different techniques (Fig. 1) including scanning electron microscopy (SEM; Fig. 1a), transmission electron microscopy (TEM; Fig. 1b), Zetasizer (Fig. 1c) and Nanoparticle Tracking Analysis (NTA; Fig. 1d)

Summary

Introduction

Exosomes are extracellular vesicles released by almost all cell types, including cancer cells, into bodily fluids such as saliva, plasma, breast milk, semen, urine, cerebrospinal fluid, amniotic fluid, synovial fluid and sputum. Their key function being intercellular communication with both neighbouring as well as distant cells. Non-coding RNA (microRNA, siRNA and piRNA) and mRNA are key cargos of exosomes [2]. Their key function being intercellular communication with both neighbouring as well as distant cells [2]. Identification of oncogenic exosomal RNA is prerequisite to the understanding of tumour pathophysiology

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Discussion

Conclusion