Research Profile

 

Welcome to the Department of cytokinetics. We had historically investigated primarily the mechanisms regulating cell proliferation, differentiation and apoptosis, in particular in tumor cells. The recent years have witnessed a shift of our focus towards a unique combination of toxicology- and cancer biology-oriented studies, which concentrate on the molecular mechanisms underlying the complex effects of toxic compounds, endogenous metabolites, or novel pharmaceuticals on tumor cell populations, as well as on their non-transformed counterparts.

The present research topics focus at the functional roles of signaling lipids (including phospholipids, polyunsaturated and short-chain fatty acids) in tumor cells, as well as the changes in lipidome accompanying transformation of tumor cells and disruption of lipid metabolism. We also investigated alterations and/or manipulations of several molecular pathways that are involved in the control of cancer cell fate, including the Ah receptor (AhR) signaling, nuclear receptors, transforming growth factor-b, death receptors or Wnt signaling pathway. Several of these pathways were also investigated in relation to toxic, endocrine-disrupting and carcinogenic action of dietary toxicants and environmental pollutants Finally, our field of interest included also the later tumorigenesis stages, tumor promotion and tumor progression. Here, a principal attention has been paid to the process of metastasis, a dissemination of cancer cells to distant body sites, which represents a massive clinical challenge in cancer research. Presently, our department primarily consists of two research groups, led by prof. Vondráček and dr. Souček, respectively, which deal with the above topics. We have also successfully established ongoing collaborations with a number of both Czech and foreign research labs/clinical centers to tackle these topics, and to develop/introduce innovative cell and animal models in our work, as well as state-of-the-art cell biology techniques.

 

Ongoing projects

Endogenous roles of the Ah receptor in control of cell fate/cell metabolism and their complex interplay with the products of gut microbiome (Vondráček lab)

Plasticity/heterogeneity of cancer cells (Souček lab)

Novel therapeutic approaches and synthetic lethality (Souček lab)

Molecular and cellular mechanisms underlying toxic effects of environmental pollutants (Vondráček lab)

 

Open positions

 

 

Endogenous roles of the Ah receptor in control of cell fate/cell metabolism and their complex interplay with the products of gut microbiome

Colorectal cancer (CRC) represents one of the most common cancer types worldwide. Metabolic reprogramming, including reprogramming of the lipid metabolism, is a part of the process of cell transformation and formation of tumor cells. Here, we focus on accumulation of specific glycosphingolipid (GSL) species, which indicates a possibility to use GSLs and the enzymes involved in their metabolism as potential colon tumor markers. Our first goal is, therefore, through using a unique combination of expertise in clinical material analyses, suitable in vitro models and a detailed analysis of cellular lipidome, to determine the principal changes in GSL composition in colon cancer tissue, to identify the enzymes responsible, and to functionally validate these enzymes in cell models derived from colon tumors. The obtained results may allow us to identify novel markers linked with the GSL metabolism in colon cancer, which may help to improve prognosis of development and progression of this disease.

Development of many cancer types is also associated with altered expression/activity of the Ah receptor – a key regulatory protein that we study, and which has been in recent years revealed to play a major role in the maintenance of colon homeostasis. We evaluate its multiple roles in the control of colon epithelium integrity and colon cell metabolism, as well as its interactions with other receptors, including PXR. The activity of the AhR in the colon tissue is tightly controlled by a vast array of bacterial metabolites, including both metabolites of tryptophan and short-chain fatty acids. The effects of such complex mixtures of microbiome products remain poorly characterized although they can have a significant impact on processes linked with regulation of inflammation, colon cell proliferation/death or integrity of epithelial barrier. Using both in vitro and in vivo models, we study both endogenous AhR ligands that are found in the intestinal environment and synthetic AhR/PXR ligands, with potential applications in the treatment of intestinal inflammatory diseases and CRC.

 

Plasticity/Heterogenenity of Cancer Cells

The cell plasticity, in tight association with stemness, contributes to the homeostasis, evolution of early neoplastic lesions, and cancer dissemination. The ability of tumor cells to adapt to dynamic changes in the microenvironment is considered to be a key requirement for their survival and outgrowth. The process which most likely interlinks the cancer cell plasticity with their dissemination capability, and adaptation to microenvironmental factors is the epithelial-to-mesenchymal transition (EMT) and other types of plasticity often associated with disease progression and therapy resistance. In our work in this area, we focused on the cell surface glycoprotein Trop-2, which is commonly overexpressed in carcinomas and represents an exceptional antigen for targeted therapy. We provided evidence that surface Trop-2 expression is functionally connected with an epithelial phenotype in breast and prostate cell lines and in patient tumor samples. We further showed that Trop-2 expression is suppressed epigenetically or through the action of epithelial-to-mesenchymal transition transcription factors and that deregulation of Trop-2 expression is linked with cancer progression and poor patient prognosis. Moreove,r we introduced a high-throughput screening platform to identify surface antigens that associate with epithelial-mesenchymal plasticity. We found specific set of surface molecules that are lost in breast cancer cells that underwent EMT in vivo and we propose that such surface signature expression reflects the epithelial-mesenchymal plasticity in breast cancer. Heterogenity and plasticity of solid cancer is represented also by its stromal compartment. Therefore, we also focused on the identification of fibroblasts and cancer-associated fibroblasts from human cancer tissue using surface markers. Regarding the plasticity of cancer cells cells, we also established and characterized two new iPSC cell lines derived from fetal and prostate cancer-derived fibroblasts which may be used for differentiation into different prostate-specific cell types in differentiation studies.

 

Novel therapeutic approaches and synthetic lethality

Cell cycle progression is closely linked to self-renewal, plasticity and cell fate decision making, allowing tissue specification, regeneration, and homeostasis. Haspin is an atypical Ser/Thr kinase with a well-described function in normal mitosis, but significantly understudied role in regulation of cell cycle interphase, plasticity and cell fate decision making. Our research is focused at elucidating differences in the Haspin interactome in interphase and mitosis, and its role in the regulation of cell cycle, plasticity, and fate. In this area we combine several state-of-the-art methodologies (advanced proteomics, unique chemical probes) into unbiased and hypothesis-driven experimental strategies with the ambition to address important gaps in our understanding of the Haspin function, molecular mechanism, and regulation in fundamental biological processes. We believe that it has the potential to advance our understanding of the precise role of this kinase in many aspects and address its attractiveness as a therapeutic target.

 

Molecular and cellular mechanisms underlying toxic effects of environmental pollutants

As a part of our long-term research program, we focus on investigation of molecular effects of important groups of organic pollutants at cellular level.  Currently, our aim is to understand the molecular basis for the effects of important groups of organic pollutants that are associated primarily with air pollution (but also life style factors, such as smoking): polycyclic (PAHs) and heterocyclic aromatic hydrocarbons (HAHs), as well as their alkyl- and oxy-derivatives. These are important environmental pollutants; however, many of them are either neglected or newly emerging groups of environmental contaminants. In particular, our understanding of effects of PAHs is still mostly limited to their carcinogenic and genotoxic action, despite numerous studies indicating that these pollutants present at significant levels in polluted air, have a much wider impact on human health.

We study their interactions with human intracellular receptors, including not only the aryl hydrocarbon receptor (AhR), which we consider to be a primary driver of their toxic action, but also endocrine and nuclear receptors, such as pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptors (PPARs), key transcriptional regulators of xenobiotic and endogenous metabolism. In line with this, we also pursue interactions of PAHs, and of their metabolites, with stress pathways underlying cellular responses to toxic insults. These toxic modes of action are particularly relevant for endocrine and metabolic disruption. There is now a considerable evidence that environmental factors may contribute to the rapid increase in the incidence of metabolic diseases, including obesity, type 2 diabetes, MAFLD or metabolic syndrome. The description of mechanisms underlying toxic effects of environmental pollutants (not just PAHs) thus represents a necessary first step for their evaluation as factors potentially harmful to human health and representing risk factors for metabolic disease, which might be also linked to chemical carcinogenesis. Since one of important factors affecting toxicity of such compounds is their intracellular metabolism, we also work on elucidation of molecular mechanisms underlying transcriptional control of xenobiotic-metabolizing enzymes contributing to bioactivation of these pollutants, in particular those under control of the above-mentioned receptors.

 

Open positions

PhD position in Cancer Research (Souček lab)

 

Join our team to study the role of Trop2 expression in metastasis.

 What we offer:

A 4-year Ph.D. position in cancer research is available under the Animal Physiology, Immunology, and Developmental Biology program at the Faculty of Science, MUNI in Brno, Czech Republic. The studentship is funded and includes a part-time grant position. Excellent administrative and technical support is provided.

Who we are looking for:

 An independent, self-motivated individual with an interest in cell and tumor biology. For more information about our research and application details, don't hesitate to contact Dr. Karel Souček at ksoucek@ibp.cz

We are looking forward to it!

Please submit your application (CV & motivation letter) before March 29th, 2024.

 

Experimentální bakalářské a diplomové práce z oblasti nádorové biologie

Laboratoř

Laboratoř je součástí Oddělení cytokinetiky na Biofyzikálním ústavu AVČR, úzce spolupracujeme s výzkumnými týmy na Přírodovědecké a Lékařské fakultě Masarykovy univerzity, máme společné projekty s kolegy z klinik Masarykova onkologického ústavu, Mezinárodního centra klinického výzkumu v rámci Fakultní nemocnice u Svaté Anny, Univerzitě packého v Olomouci i s řadou zahraničních týmů, např. na Medical University Innsbruck.

https://www.ibp.cz/en/research/departments/cytokinetics/info-about-the-department

Naším hlavním výzkumným zájmem je porozumět plasticitě a heterogenitě nádorových buněk a roli nádorového mikroprostředí v regulaci progrese rakoviny. Buněčná plasticita je považována za faktor, který přispívá k rezistenci vůči chemoterapii rakoviny a ke špatné prognóze. Zároveň se předpokládá, že recidiva a chemorezistence mnoha typů rakoviny jsou silně spojeny s biologií nádorovým kmenovým buňkám podobných buněk nebo nádorových iniciačních buněk a cirkulujících nádorových buněk. Naší snahou je lépe porozumět molekulárním mechanismům spojeným s plasticitou buněk a její úloze při progresi rakoviny a vzniku buněk zodpovědných za letální formu nádorového onemocnění.

Co nabízíme

Příležitost stát se plnohodnotným členem vědeckého týmu. Můžete se naučit se řadu základních i pokročilých metod z oblasti nádorové biologie, se kterými najdete uplatnění jak ve vědě, tak v rutinní praxi (průtoková cytometrie, qPCR, atp.). Budete mít možnost zapojit se do našich výzkumných projektů a podílet se na vědeckých publikacích. Získáte kompetitivní téma pro svou bakalářskou nebo diplomovou práci, kombinující potřeby našeho týmu a váš zájem. Podpoříme vás při přípravě vlastního výzkumného projektu - např. v rámci GAMU. Ukázka úspěšně řešených témat:

BP

https://is.muni.cz/th/zl62a/

DP

https://is.muni.cz/auth/th/zli68/

https://is.muni.cz/auth/th/f5nxa/

https://is.muni.cz/auth/th/pu943/

Co očekáváme

Zájem o vědeckou práci, pečlivost, zodpovědnost, trpělivost, motivaci učit se nové věci, chuť dělat i něco navíc a zapojení do fungujícího týmu.

Co vás čeká

Po úvodním pohovoru se domluvíme na zkušebním období, kdy chodíte do laboratoře, abyste viděl/, zda Vám sedí náš styl práce a komunikace. Seznámíte se se základními metodami, uvidíte jak fungují naše semináře a pracovní schůzky, dostanete „lab manual“, kde jsou popsány základní principy fungování laboratoře. Pokud jde vše dobře a sladíme vzájemná očekávání, potom najdeme projekt, kterého budete součástí. Pod vedením zkušeného kolegy/kolegyně si začnete prakticky osvojovat experimentální metody (kultivace buněk, analýza proteinové a genové exprese, práce s experimentálními zvířaty nebo klinickými vzorky atp.) a metody vědecké práce (vedení laboratorního deníku, zpracování protokolů, analýza a prezentace dat). Pokud jste šikovný/á a bude vás to bavit, nabídneme vám možnost letní brigády v laboratoři a na podzim specificky pro vás vypíšeme konkrétní téma BP/DP.

Naši absolventi

https://www.sci.muni.cz/ofiz/absolvent-ofiz-jan-remsik-v-prestiznim-zebricku-forbes-30-pod-30/

https://ueb.sci.muni.cz/aktualne/nas-absolvent-v-zebricku-forbes-30-pod-30

Pokud Vás tato možnost zaujala a chcete zjistit více, kontaktujte Dr. Karla Součka a domluvte si osobní schůzku, ksoucek@ibp.cz, https://orcid.org/0000-0001-7283-8150