“I love sEV” is written on the coffee cup used by Meike Saul, head of a research group in the Department of Biology at TU Darmstadt. “It was a gift from my doctoral students”, she says and explains that the abbreviation sEV stands for “small extracellular vesicles”: “They are small bubbles discharged from cells.” It used to be thought that these vesicles acted as mini garbage trucks for unwanted substances but we now know that they also play a key role in intercellular communication. “Our cells have to coordinate their actions with one another, not only in healthy tissue but also in tumours”, says Saul. For this purpose, they fill these small vesicles – also known in technical jargon as exosomes – with messenger substances, which notably include lots of small RNA molecules.
“I love miR-574-5p” would also be a good slogan for Saul’s coffee cup. This abbreviation describes a short strand of RNA – a so-called microRNA (miRNA). Saul recognised how important this particular microRNA was almost ten years ago and it has been the main focus of all of her subsequent projects to this day.
Surprising discovery of the 574th microRNA
MicroRNAs help to determine which proteins a cell produces and which it does not. Although they do not contain any construction plans for these proteins, they can bond with standard RNAs and influence the protein synthesis in our cells in that way. Several thousand miRNAs have now been identified in humans alone. Since they were first discovered in 1993, these short strands have been numbered consecutively. Saul came across miRNA number 574 as a postdoc at the renowned Karolinska Institute in Stockholm. She can still recall the moment she noticed the sequence as she was sat at her desk: “It was purely an accident and at the same time extremely lucky to find this microRNA because it regulates a really essential process that plays an important role in many illnesses.” The microRNA with the number 574 influences the synthesis of prostaglandin E2, a tissue hormone that helps to control illnesses such as cancer and arthritis and also our pain perception, no matter whether it is rheumatism, a headache or a cut.
Development of a micro-RNA test for better cancer therapy
Saul’s group recently discovered how miR-574-5p interacts with prostaglandin E2 in the most common form of lung cancer – non-small cell lung cancer. Her team is currently developing a diagnostic method to improve the treatment of this type of cancer in cooperation with the testing laboratory Prolytic in Frankfurt, which is part of the Kymos Group. Prostaglandin E2 drives the growth of the tumour in most people suffering with this cancer. Medicines such as aspirin that have a counteractive effect on prostaglandin E2 could thus be used to support standard cancer therapies. “Unfortunately, the tumour-inhibiting effect of prostaglandin inhibitors does not occur in all patients”, says Saul. To ensure that cancer patients are not unnecessarily burdened by an additional medicine, it is important to ask the following question: Which patients will be helped by administering prostaglandin inhibitors? Saul believes that the answer can be found by measuring the presence of miR-574-5p in the blood. Her most recent study shows that the amount of this miRNA is related to the prostaglandin values in the tumour. To validate the blood tests, Saul’s group is now working together with Prolytic and the University Hospital in Gießen on a clinical study with 150 lung cancer patients. If everything runs according to plan, a test for personalised cancer medicine will be ready to launch on the market in around two years. The idea is for Prolytic to test the samples as a diagnostic service.
Method is also important for early cancer detection
Saul is already thinking one step further. She wants to combine measurements of miRNA and exosomesso that it will be possible to detect the cancer in the blood at an early stage – possibly even in other body fluids. This is known as a liquid biopsy. If a patient has a suspected tumour, a special needle has so far always been used to collect a tissue sample. This traditional biopsy, which many people find uncomfortable, could be replaced by the blood test. In order to achieve this aim, Saul’s group is now analysing exosomes in more detail. “Based on the surface proteins found in these small vesicles, we can find out from which bodily tissues the exosomes originate and whether they were released by healthy or diseased cells”, explains Saul. Her group uses a piece of equipment called Exoview and specially prepared antibody chips to examine the exosomes. A little of the blood or another liquid sample is dripped onto the chips and the exosomes bind to the antibodies fixed on the chip based on the lock and key principle. The bonds that are formed appear as different coloured fluorescent dots when examined in Exoview and these patterns of light could be used to detect cancer.
My projects all sound very different from one another but actually they always have exosomes and microRNAs in common.
Saul is not only carrying out research into new diagnostic methods but also innovative therapies. She already has many ideas for new medicines to combat lung cancer and is already carrying out tests on animals for an RNA drug to combat arthritic pain in cooperation with the Karolinska Institute in Stockholm. Saul is also thinking about how to use exosomes as a transporter for pharmaceutical substances. “My projects all sound very different from one another but actually they always have exosomes and miRNAs in common”, she admits.
Increased interest in microRNA technologies
The coronavirus pandemic has delayed some of Saul’s projects but at the same time increased the general understanding of her research because terms such as RNA, surface proteins and PCR technology, which is also used to identify microRNAs, are things everybody is talking about: “My ideas for new therapies and diagnostic tests based on miRNAs were not always taken seriously a few years ago”, she says. “However, pharmaceutical companies are now extremely interested in them.”
This growing interest is also having a positive impact on Saul’s research budget, which was already impressive. Her group has attracted around 1.2 million euros in third party funding over the last five years. For example, Saul financed the purchase of the Exoview equipment with the support of the Wilhelm Sander Foundation, which funds innovative research into cancer. In November, she was awarded the Dr. Hans Messer Foundation Prize for her scientific achievements together with Vera Krewald, a Theoretical Chemistry Professor at TU Darmstadt. Saul intends to use the prize money of 25,000 euros primarily to continue her analysis of exosomes and thus come a step closer to achieving her aim of being able to detect cancer using liquid biopsies.
Julia Donzelli, Eva Proestler et al.: Small extra-cellular vesicle-derived miR-574-5p regulates PGE2-biosynthesis via TLR7/8 in lung cancer, Journal of extracellular vesicels, October 2021