Eva Budinská is a trained mathematical biologist. She obtained a doctorate in oncology and continued with postdoctoral studies at the Swiss Institute of Bioinformatics in Lausanne, where she spent four years. In her scientific field, she operates at the intersection of data analysis and biology, meaning her task is not only to process data but also to interpret it. Specifically, she focuses on analyzing molecular and imaging data in oncology, particularly colorectal cancer. Besides doing research, she is also the guarantor of the Biomedical Informatics program – a specialization in the Mathematical Biology and Biomedicine program at the Masaryk University Faculty of Science. In the interview, she explains what exactly her cancer research entails, where it is headed, and why connecting it with the microbiome is essential.
What do you specifically focus on in colorectal cancer research?
I focus on the analysis of experiments that we set up in collaboration with the Masaryk Memorial Cancer Institute (MMCI). Essentially, we collected a lot of different types of data from nearly two hundred oncology patients, allowing us to look at colorectal cancer from various perspectives. We observe the patients’ gut microbiome, which bacteria are directly in the tumor, or how the tumor manifests molecularly, i.e., whether and what genetic mutations it has, which genes are turned off or on, and in which areas of the tumor. We then try to put it all together to gain new insights that would help us better understand tumors and determine what treatment would be appropriate, or at least how long the patient will live. Based on the microbiome's composition in the stool, we also attempt to determine whether the patient has cancer at all, which could spare them an unpleasant colonoscopy used to confirm suspected colorectal cancer.
How are these data for tumor research obtained?
For such extensive research, collecting many different types of samples is necessary. We asked patients for a stool sample and took swabs from the tumors and adjacent healthy tissue during surgical removal of the tumors. These are then analyzed using sequencing and other methods to determine which bacteria are present. After the tumor is removed, it is embedded in a paraffin block and sliced into thin sections placed on microscope slides. The sections are then stained and examined under a microscope by a pathologist to determine whether it is a tumor, how advanced it is, whether there are immune cells, what type they are, and so on. These same slides are then digitized using a scanner into images that we analyze automatically using artificial intelligence. Molecular technologies are then used to determine whether there are mutations in the tumors or whether other molecular processes are occurring in them.
Everything is eventually put together, and we look for potential associations. For example, we are developing methods for detecting signs in the tumor image indicating a mutation without having to confirm it molecularly.
You pay special attention to the microbiome in your current research. Do you already have any findings on how it affects cancer development?
Interestingly, oral pathogens that cause, for example, gum inflammation are very often found in tumors. There is a theory that if our gut is somewhat damaged and our microbiome is somehow imbalanced, these oral pathogens can settle in it and cause a tumor or worsen existing cancer. We have so far confirmed that these types of bacteria are indeed present and that their presence is associated with higher tumor stages and overall worse survival. It is known that bacteria produce substances capable of influencing the immune system, thereby helping the tumor to hide from it. When the immune system cannot find the cancer, it cannot fight it.
Can we prevent cancer by supporting our microbiome?
It is not as simple. Cancer development is multifactorial. It also depends on the type of cancer. Even colorectal cancer is not a single disease; the prognosis varies considerably depending on which side of the colon the tumor is located. The distribution of gut bacteria also varies. Right-sided tumors are more likely to have pathogens originating from the mouth, while left-sided tumors are associated with a lack of commensal, i.e., beneficial, bacteria. We also know that bacteria affect cancer treatment, especially immunotherapy. We are trying to understand better which bacteria are found where and how this relates to tumor aggressiveness, and patients’ responses to treatment. We also look at tumor and bacterial metabolism because the metabolic products of bacteria influence their surroundings.
How does the ONCOBIOME project, which deals with the relationship between the microbiome and cancer and in which RECETOX is also involved through your research group, add to these known facts?
The ONCOBIOME project is an international research initiative focused on linking the microbiome and cancer. The project aims to determine the specific composition of the gut microbiome that can influence the development, prognosis, and response to treatment of various types of cancer, such as breast, lung, colorectal, and melanoma. We were fortunate to evaluate and expand our previous Gutbiome project within it, in which we, together with the MMCI, collected a uniquely extensive dataset thanks to the extensive efforts of their experts. In the project, we are leading a work package focused on analyzing many types of data, i.e., multiomics analysis, which I described above. The goal is to create new diagnostic and prognostic tests that could be used to predict the development of cancer, its course, and its response to treatment. Our hypotheses are then examined within the project, and we investigate how the gut microbiome affects the host’s metabolism, immune responses, and processes leading to cancer. The aim is to find new possibilities for the prevention and treatment of cancer using probiotics and prebiotics. Perhaps most importantly, ONCOBIOME aims at practical applications in clinical oncology.
Compared to previous research, we now use a more precise method in the project, allowing us to more accurately determine the types of bacteria in the gut and tumor. However, it is necessary to consider that even when using the most modern technologies, something may still escape us. The sequencing method used, where the examined DNA is divided into smaller pieces that are then read sequentially, is essentially like a puzzle. Moreover, the sequencer performing it has only a certain capacity, so some data may be missed. Just like when a fisherman throws a net into a lake, it is more likely to catch larger and more common fish than rarer species.
Returning to the microbiome, how much does it influence the development of colorectal cancer?
It cannot be determined unequivocally; it is always a mixture of factors that differ among patient. Many things influence the development of a tumor; the microbiome is not the most important, but it is certainly significant. These influences need to be studied holistically. In another European project, DISCERN, in which RECETOX participates, we investigate, together with Petra Bořilová-Linhartová’s research group, the relationship between mutations in colorectal and pancreatic tumors, bacteria present in these tumors, and the patients’ living environments, including exposure to toxic substances. In the SALVAGE project, we focus on tumor-host interactions and the tumor microenvironment. We also hope to succeed in a project where we want to further investigate the impact of probiotics on patients and the side effects of chemotherapy.
I still don’t quite understand why you decided to focus so much on the microbiome in your research?
Because I felt it made sense; it was another piece of the puzzle we were missing. Colorectal cancer is very diverse; different treatments work for different patients, and the speed of its progression also varies. During my research in Switzerland, I found interesting relationships between various molecular processes in colorectal cancer, tumor aggressiveness, and patient survival. They pointed to the immunological and morphological profile, i.e., how the tumor and its cells appear. Therefore, automatic analysis of tumor images was added, but it still was not enough. Decades of research in this area have shown that molecular data can only partially help in personalized medicine. We are still trying to find answers on how to treat cancer better while reducing side effects and mortality rates. Without understanding the underlying mechanisms, we will not achieve this. And here comes the microbiome. It is a topic we hear about everywhere now. We can now study the microbiome on a large scale much better than we ever could. New approaches have allowed us to look into the gut and discover anaerobic bacteria not commonly grown in the lab because of their inability to survive in the presence of oxygen. Adding the microbiome to research is logical because it significantly interacts with the immune system, which is key to cancer treatment. We must study it because, without it, we will not make progress.
Why is the immune system essential for treatment?
Immunotherapy has proven to be very promising within the existing cancer treatment modalities. In immunotherapy, we train our cells to recognize tumor cells. The tumor is like a mafia; it hides, and we can only roughly estimate its center. Destroying tumor cells can be achieved by bombarding them with chemotherapy, which is the first strategy, but this modality is highly non-selective, leading to the destruction of many healthy cells, so we lose civilians. Moreover, cancer cells are resilient and can hide with the help of some bacteria; thus, they will not all be destroyed, they have shelters; they are resilient enemies. In contrast to chemotherapy, immunotherapy is a targeted therapy in which our immune system is trained to. So, we train our own special police that infiltrates among civilians and recognize cancerous cells - mafia members with a fake ID. However, as was earlier described, several bacterial species “help” tumor cells avoid the immune system, thereby preventing their destruction, they can divert the attention of the special police. We can facilitate the treatment process when we find out which bacteria are problematic and which help alert immune cells. We hope that the result of the ONCOBIOME project mentioned above will be the creation of such a strategy. The first results show that it works, which brings me much joy. I see that we are making progress.
What do you think is the biggest obstacle in cancer research?
People are not laboratory mice so we will never know exactly everything we need. For example, we cannot observe how far cancer will go if we do not treat it. We cannot test what effect it will have on development if I add this or that bacterium. Moreover, it is difficult to determine what a truly healthy microbiome is. To confirm that someone is really healthy and does not have colorectal cancer, they would have to voluntarily undergo a colonoscopy. And no one will do that. So, there will always be a certain gap in what we know about cancer.
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