The role of extracellular vesicles in cell-to-cell communication in the context of disease
Extracellular vesicles have been shown to contribute to the metastasis of melanoma and to the spread of viral infection. We discuss their potential in diagnostics and personalised medicine.
With the rapid expansion of the field of extracellular vesicle (EV) research, these nanoscale particles have been implicated in a wide variety of diseases and conditions including cancer and viral infection. Dr Evelyn Lattmann is a research fellow with a postdoctoral appointment at the University of Zurich and is currently on secondment in the US. Her interest is in EVs and their role in the progression and metastasis of melanoma as well as Covid-19 infection.
With a background in cancer research, particularly cell-to-cell communication and the metastasis of melanoma, Dr Lattmann’s work has recently evolved to focus on translational cancer research, which aims to bridge the gap between lab and clinic by using the findings of fundamental research to develop potential therapeutics. Dr Lattmann is currently analysing circulating tumour cells and exosomes in biofluids to identify potential biomarkers of disease and gain insight into the mechanisms underlying metastasis and cancer-cell invasion. A major driving factor in Dr Lattmann’s research has been her interest in finding non-invasive methods of diagnosing and treating conditions including cancer. Due to their presence in blood and other biological fluids, exosomes were an attractive target for this research.
For their analysis of EVs, the group are using Izon’s qEV Isolation columns and confirming the identity of exosomes with proteomics. To determine biomarkers, the group extract the RNA cargo of the vesicles using Izon’s RNA Extraction kits and have obtained promising results from subsequent next generation sequencing. As well as RNA, Dr Lattmann also explains that mutations in EV DNA can be identified in samples from patients with melanoma; therefore, analysing the entire molecular profile of EVs is particularly informative. Unravelling the roles of EV cargo in cell-to-cell communication and the underlying biology may enable the use of EVs as therapeutics; Dr Lattmann believes that EVs have wide potential in clinical application, stating that “there are many possible uses of exosomes” in both diagnostics and treatments.
Image 1 - Dr Evelyn Lattman
The specific roles of EVs in viral infection are complex and elegantly interlinked, involving immunoregulatory effects and modulation of cell-cell communications. While these effects can protect the host from viral infection1, there is growing evidence that viruses take advantage of EV pathways; virus-infected cells release EVs with specific molecular signatures2 which then influence the immune response of the host and contribute to the spread of viral infection. With the intrinsic link between EVs and viral infection, elucidating the role of EVs in Covid-19 infection is a high priority in current research, and her interest in liquid biopsies (Figure 1) led Dr Lattmann to begin looking at the molecular profile of EVs from patients with Covid-19 infection with the aim of identifying biomarkers and possible diagnostic markers. This research is still in the early phases; Dr Lattmann states that “at the beginning it is difficult to say in which direction it will go”, explaining that the research has begun with an unbiased approach and as soon as specific markers are identified they will dive into the biology; however, she believes that there will be positive findings and we look forward to seeing what the data show!
Figure 1. Liquid biopsies offer a quick, simple, and minimally invasive method of obtaining a comprehensive analysis of a patient’s health status. In oncology, circulating tumour cells and cell-free DNA are typically analysed to diagnose cancer or assess the stage of disease. Recently, extracellular vesicles in biofluids have become a focus of much research as potential biomarkers. .
From a background of working with Caenorhabditis Elegans (a millimetre-length worm which can be observed with a light microscope), it has been an interesting transition for Dr Lattmann to now work with less tangible entities, and it has not been without challenges! The scarcity of material within and on EVs (RNA and protein) can make analysis difficult, and plasma and other biological fluids contain EVs from all organs of the body as well as from distinct biogenesis pathways, meaning that it is hard to filter out the EVs of interest from the complex milieu. While Dr Lattmann explains that it would be wonderful to be able to visualise EVs with live imaging and follow their pathways in the body, she does not believe that the current challenges will limit the field as new techniques which promise to circumvent these obstacles are rapidly emerging.
The work that Dr Lattmann and colleagues are carrying out has huge potential implications and will open up many future avenues for research. The future directions will depend on the outcomes of the current research, but Dr Lattmann suggested that the analysis of other biological fluids (beyond plasma) could be a future focus, which could increase the scope of research and reveal more EV-based biomarkers and treatments for various diseases including cancer. Furthermore, artificial skin models developed by Mitch Levesque and used by Dr Lattmann and colleagues use at the University of Zurich could enable functional experiments and test biological hypotheses arising from the current research, as well as potentially examining therapeutic responses to EVs as treatments. Dr Lattmann is excited to be able to continue her EV research in future posts, and mentions that the portability of Izon’s products will make the continuation of her research easy.
Personalised medicine (also known as “stratified” or “precision” medicine) involves grouping patients based on risk of disease or response to therapy using diagnostic tests or techniques3. Dr Lattmann believes that EVs could be powerful tools in this approach. The therapeutic response is very diverse among patients with melanoma; for example, the level of circulating exosomal PDL-1, a protein that allows tumour cells to evade immune surveillance, could be used to categorize patients as clinical responders or non-responders to immunotherapy 4. In addition, tumour EVs have been shown to prepare the pre-metastatic niches5. Therefore, analysing EVs of patients with melanoma could help to predict the disease course and inform clinical decision making with regards to treatment regimens, leading to improvements in patient care and outcomes.
While their research is in the early stages, the work of Dr Lattmann and her fellow researchers recognise the wide potential of EVs, with applications ranging from diagnostics to treatments; analysis of EV biomarkers in patients could be used to generate tailored therapeutic regimens/stratify patients for treatments. Dr Lattmann highlights the many uses of EVs; while interest and knowledge in the exosomes is rapidly increasing, the field is still in its infancy but she believes that the potential of these vesicles as therapeutic agents is highly important and as this becomes more well recognised we will begin to see EV-based therapeutics being used in the clinic.
- Ñahui Palomino RA, et al. Extracellular vesicles from symbiotic vaginal lactobacilli inhibit HIV-1 infection of human tissues. Nat Comm 2019;10:5656.
- Meckes DG, et al. Modulation of B-cell exosome proteins by gamma herpesvirus infection. Proc Natl Acad Sci 2013;110:E2925–E2933.
- FORUM Academy of Medical Sciences. Stratified, personalised or P4 medicine: A new direction for placing the patient at the centre of healthcare and health education (May 2015) [Internet]. 2015
- Chen G, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 2018;560:382–386.
- Hoshino A, et al. Tumour exosome integrins determine organotropic metastasis. Nature 2015;527:329–335.