June 2025 in Science at our faculty
We bring you a selection of the most interesting things in science and research at our faculty in the first summer month.
Bespoke models - Unique biobank helps pancreatic cancer research
Specific treatment for a specific patient - this is the basic principle of precision medicine, an increasingly advanced therapeutic concept, especially in oncology. However, being able to predict exactly how a patient will respond to therapy remains a difficult goal to achieve. Oncologists at the University Hospital Brno are being assisted in their search by the research group of Petr Vaňhara from the Department of Histology and Embryology at the Masaryk University Faculty of Medicine. Associate Professor Vaňhara is interested in cellular plasticity and tissue regeneration, and the development of tissue models derived from stem cells. He is also the principal investigator of a project focused on pancreatic cancer, the output of which will be a unique biobank of living pancreatic tumour cells, which will be used to create three-dimensional tissue models on which scientists can study the processes behind the growth of tumour cells. And in a multidisciplinary collaboration under the banner of the Centre for Precision Medicine, which was introduced last year, these findings will gradually be transferred into clinical practice.
You are the principal investigator of a project whose full title is Development of ex-vivo cell models for pancreatic adenocarcinoma: markers and targets for precision medicine, and the development of these models goes hand in hand with the creation of a biobank of characterised cell lines. How does this project fit into the broader context of your work at the Department of Histology and Embryology?
The long-term scientific focus of the Department of Histology and Embryology is primarily on understanding stem cell biology with the aim of using them for tissue engineering and regenerative medicine. This particular project focuses on the histogenesis of abnormal tumor tissues. It brings together the clinical expertise of colleagues from the Surgical Clinic and the Internal Hematology and Oncology Clinic of the University Hospital Brno and our biological and technological background. Cells obtained from native pancreatic tumour samples allow us to recapitulate the tumour microenvironment and intercellular interactions thanks to advanced culture techniques. Our goal is to reveal differences between tumor development in individual patients, to contribute to the understanding of their clinical and biological heterogeneity, and to identify molecular mechanisms that may represent potential targets for specific therapies.
Why did you focus on pancreatic disease?
Pancreatic cancer has a very unfavourable prognosis based on the aggressive nature of the disease and frequent resistance to chemotherapy. Moreover, the disease does not manifest itself for a long time and is often discovered only when it is too late for effective treatment. The median survival of patients with pancreatic cancer is in the order of months rather than years. In addition, pancreatic tumours, which have long been more typical of older patients, are increasingly being found in younger people, where they may behave biologically differently. Understanding how pancreatic tumours arise and develop is clearly contributing to the development of advanced targeted treatments.
What are you particularly interested in?
We are interested in the three-dimensional arrangement of the tumour, and the properties of the cells that make it up. Pancreatic tumors are characterized by a highly fibrous, desmoplastic stroma, which creates a unique and relatively inhospitable environment for the tumor cells themselves. Nevertheless, they are able to grow and adapt to it, and can cope with, for example, cellular or tissue stress induced by cytotoxic treatment. We are interested in the molecular response of cells to stress conditions in tumor tissue, what signaling pathways are activated during these conditions and how they could potentially be targeted, as well as what the differences are between tumors of different patients.
“Thanks to unique collaborations with clinical sites, we have recent, unique cellular material at our disposal.”
Petr Vaňhara
How does such 3D modelling work?
Cultivating cells in three-dimensional conditions allows for better mimicking of intercellular interactions and inter-arrangements than in a single layer on a conventional petri dish. There are different ways to recapitulate tumor histogenesis in vitro. From simple pure tumor lines that form homogeneous "spheres" to sophisticated cocultures of different cell types. Such a model may already contain tumor cells, stromal cells and even various vascular fragments. There are many more or less sophisticated three-dimensional models.
To what extent are you currently able to mimic in vitro and in vivo conditions and answer your scientific questions with these 3D models?
We are currently looking at how the structure of the connective tissue that tumor and stromal cells form around themselves differs, what their biological and biomechanical properties are, and how tumor cells respond to it. It is for this research that we use cells derived from tumor tissue, which we culture in a three-dimensional environment, as spheroids consisting of several hundred cells that interact biochemically and biophysically to determine the biomechanical properties of the entire spheroid.
How do you then use these models to find out how a real tumour might behave?
We look at selected molecules, but also at recurring patterns of spheroid growth under different conditions and try to associate them with clinical data from patients. As a result, for example, we have already been able to identify some proteins that we know affect the composition of the intercellular matrix or the cellular response to cellular stress, and which have also been associated with patient survival in large genomic studies. We are trying to explain what is behind these biological processes.
Which, in combination with other data, can perhaps facilitate diagnosis?
Yes. But it may first of all make it easier to understand what is happening during tumour development. It can help answer the question of why some tumours are more aggressive than others, or why survival is weeks or short months for some patients and significantly longer for others, even though they have the same initial conditions. It may also reveal other signaling pathways that can be targeted, and last but not least, it contributes as another element of the mosaic to precision medicine, which we are trying to develop intensively in Brno.
To what extent can this help predict how a patient will respond to treatment?
The concept of taking a patient's cancer cells, experimentally testing how they respond to a chemotherapy drug, and determining whether the patient will respond to the treatment is decades old. But despite being this straightforward, it surprisingly doesn't work in clinical practice. The structure and composition of the tissue microenvironment is disproportionately more complex than laboratory conditions and probably plays a key role in the ability of cancer cells to escape treatment. We would, of course, love it if our cell models could show how a given patient will respond to a particular treatment setup or predict the course of the disease. We do see differences in the ability of cells derived from tumor tissue from different patients to recapitulate tumor development in vitro, but practical application is still a long way off. Although this is one of the principles of precision medicine, where knowledge of the biological characteristics of the tumour leads to tailored treatments for specific patients.
Histology
Histology is one of the first subjects a medical student encounters at the Faculty of Medicine. Its content is the understanding of the microscopic structure and function of tissues and organs, and an integral part is the study of microscopic histological specimens, either at the microscope or in a virtual atlas. However, modern histology also includes many aspects of cell and tissue biology and their applications in tissue engineering, regenerative medicine or oncology.
As a layman, how do I imagine the physical form of the biobank being created and what are its advantages over other similar sets?
It is a container containing tubes containing live cells isolated from surgically removed pancreatic cancer tissue, and frozen in liquid nitrogen vapour, at -196°C. Each sample is recorded in a database containing a range of clinical, biological and pathological data. Thus, not only do we have cells from a specific patient's tumor, but we also know the clinical and pathological background of the tumor. The vast majority of cancer research in recent decades has been conducted on tumour cell lines, which are cells that have been isolated from a tumour and grown without restriction in cell culture. Such cells are extremely useful and represent a unique tool for studying the molecular biological context of tumors. However, they have an obvious drawback. Established lines are limited in number which means that they do not reflect the full breadth of a given disease in a population, and by being cultured for decades, they inevitably undergo phenotypic shifts. Thus, the cells may not match the characteristics of the original tumour in many parameters. Thanks to unique collaborations with clinical sites, we have recent, unique cellular material at our disposal. We use them in experiments for a limited period of time so that we avoid unwanted changes or contamination.
So the point is not to make a stock that lasts for many years, but one that needs to be continuously renewed...
Yes, that's the principle of biobanks. Biological material is continuously entering and leaving each biobank at the request of various researchers. This is another goal of our project. To offer researchers an easily accessible local, dedicated repository that can support various scientific projects related to pancreatic cancer. Our samples are very close in nature to the original tumor material from which they originated. Compared to commercially available tumour lines, they can thus better answer specific scientific questions. This is the uniqueness of our biobank and three-dimensional models.
The project is about halfway through, what have you achieved so far?
First of all, standardised procedures for how we isolate, expand and study cells. We have a clear idea of the cell types we get from tumours and we have a database to support this. These efforts of ours are slowly starting to generate publications that are gradually piecing together a comprehensive picture of pancreatic tumor development.
What is your ideal realistic goal?
Understanding what is behind the etiopathogenesis of different pancreatic tumors that behave differently in different patients. This can also contribute to effective diagnosis and treatment. This means that if we identify a parameter that correlates with lower patient survival, this can be the start of further studies to confirm, refute or extend this knowledge, and can become part of a therapeutic or diagnostic portfolio.
How is your collaboration with clinicians going?
The surgical team is led by Professor (Zdeněk) Kala, who is responsible for all clinical aspects, from planning and performing the surgery to the logistics of the specimen. Fellow oncologist, Dr. Michael Eid, is in charge of the oncology and clinical part, especially the annotation of patient samples. Colleagues from the Department of Pathology - Dr. Jakub Vlažný - perform the histopathological diagnosis and then we receive the residual material from the tumor bed for in vitro expansion. So it's a circle that is working very well at the moment, especially because of the commitment of the whole broad team. (smiles)
