Department of Cancer Biology

Research Topic

Physiological factors in tumor microenvironment, namely hypoxia and acidosis, considerably contribute to cancer progression. Hypoxia results from insufficient oxygenation of tumor cells through aberrant and non-functional blood vessels and leads to acquisition of aggressive tumor phenotype, including resistance to chemotherapy and radiotherapy as well as to increased invasiveness and metastatic propensity.

Hypoxia also supports oncogenic metabolism generating excess of acidic products, such as lactate ions, protons and carbon dioxide, which are eliminated from cells through ion transporters/exchangers or by intracellular neutralization with bicarbonate ions. This allows for neutralization/alkalinisation of intracellular pH and acidification of extracellular pH. Acidosis has similar phenotypic effects as hypoxia and therefore, detection of both hypoxia and acidosis in tumors is clinically relevant.

We investigate tumor hypoxia and acidosis in order to better elucidate molecular mechanisms of cancer cell adaptation to these stresses in tumor microenvironment with particular focus on carbonic anhydrase IX (CA IX) that was identified and cloned in our institution, and our team has considerably contributed to its molecular and functional characterization and to production of specific monoclonal antibodies and other reagents for CA IX research and clinical applications.

CA IX is induced by hypoxia and plays a role in tumor acidosis. It is primarily localized on the cell surface, where it controls pH and supports survival and invasiveness of tumor cells. It can be also released to body fluids via mechanism of ectodomain shedding. Expression of CA IX is strongly associated with cancer and is currently used worldwide as a biomarker of hypoxia and acidosis in diverse tumor types with potential prognostic and/or predictive value. CA IX is also under clinical development as promising therapeutic target.

Our recent research interests include the role of CA IX in tumor metabolism, in metastatic cascade and in signalling pathways supporting cancer progression. We also investigate effects of drugs and inhibitors on expression levels and activity of CA IX. Our major goal is to open new avenues of CA IX use in diagnostics and therapy.

 

Research Team

Mgr. Eliška Švastová PhD.

Head of Department

02/ 59 302 404


PRINCIPAL INVESTIGATORS:

prof. RNDr. Silvia Pastoreková, DrSc.

MVDr. Juraj Kopáček, DrSc.

EMERITUS:

prof. RNDr. Jaromír Pastorek, DrSc. (professor Emeritus) – co-founder of cancer-associated protein CA IX; long-term member of the team and head of Department of cancer biology (1992 – 1998), former director of Institute of Virology of SAS (2001 – 2009) and President of Slovak Academy of Sciences (2009 – 2014)

RESEARCHERS:

RNDr. Monika Baráthová, PhD., Deputy Head of Department, group leader

RNDr. Lucia Csáderová, PhD.

RNDr. Adriana Gibadulinová, PhD.

PharmDr. Tereza Goliaš, PhD.

RNDr. Martina Labudová, PhD.

RNDr. Ingeborg Režuchová, PhD.

RNDr. Martina Takáčová, PhD.

RNDr. Miriam Zaťovičová, CSc., group leader

SCIENTIFIC STAFF:

RNDr. Mária Bartošová, PhD.

RNDr. Petra Belvončíková, PhD.

RNDr. Katarína Grossmannová, PhD.

Mgr. Ivana Kajanová, PhD.

RNDr. Ľubomíra Lukáčiková, PhD.

RNDr. Veronika Šimko, PhD.

Mgr. Lucia Škvarková, PhD.

SCIENTIFIC AND TECHNICAL STAFF:

Ing. Alžbeta Idunková

Mgr. Lenka Jelenská

Mgr. Oľga Sedláková

PhD. STUDENTS:

Mgr. Eva Kocianová

Mgr. Veronika Lelkesová

Mgr. Jana Lapinová

Ing. Barbora Puzderová

Mgr. Sabína Strapcová

External PhD. Students:

MUDr. Silvia Fečíková, št. odbor Onkológia, LF UK, ext. pracovisko NÚTPCH a HCH Vyšné Hágy

LABORATORY:

Jana Išová

Alena Kosorínová

Kvetoslava Tarábková

Projects of SRDA (Slovak Research and Development Agency)

Elucidation of novel pro-metastatic functions of tumor-associated carbonic anhydrase IX and its cross-talk with proinflammatory response. Project code: APVV 14-0816. PI: Eliška Švastová. Duration: 2015-2019.

The role of CA IX in adaptation to tumor microenvironment and in resistance to anticancer therapy: molecular mechanisms and clinical implications. Project code: APVV 15-0697. PI: Silvia Pastoreková. Duration: 2016-2020.

Activity Assay of Transfer Factor, Immunostimulatory Drug from Leukocytes Extract And Its Preparation Standardization. Project code: APVV 15-0720, PI: Juraj Kopáček. Duration: 2016-2020.

Impact of comorbidity therapy on tumorigenesis and a role of the tumor microenvironment in this process. Project code: APVV 16-0343, PI: Monika Baráthová. Duration: 2017-2021.

Cell-in-cell phenomena as microevolutionary processes in cancer progression: a role for hypoxia-induced carbonic anhydrase IX. Project code: APVV 19-0098, PI: Silvia Pastoreková, Duration: 2020-2024.

Projects of VEGA (Scientific Grant Agency of the Ministry of Education, of the SR and the Slovak Academy of Sciences)

Development of 3D co-culture systems integrating several components of tumor microenvironment and study of their influence on the course of anti-tumor therapy. Project code: VEGA (2/0064/18), principal investigator: Lucia Csáderová. Duration: 2018-2021.

Regulation of pyruvate dehydrogenase kinase 1 activity in the control of glycolytic metabolism in hypoxic tumors. Project code: VEGA (2/0078/19), PI: Tereza Goliaš. Duration: 2019-2022.

Study of pro-metastatic functions of carbonic anhydrase IX, relationship between CA IX and mucins and hypoxic microenvironment in pancreatic cancer. Project code: VEGA (2/0105/19), PI: Eliška Švastová. Duration: 2019-2022.

Unraveling the mechanisms linking obesity and cancer progression: the interplay between adipocytes and cancer cells. Project code: VEGA (2/0076/20), PI: Martina Takáčová. Duration: 2020-2023.

Effect of combination therapy with carnosine on tumorigenesis in colorectal carcinoma models. Project code: VEGA (VEGA 2/0090/20), PI: Monika Baráthová. Duration: 2020-2023.

Carbonic anhydrase IX as one of the key components of exosomes secreted from cancer cells. Project code: VEGA (2/0074/20), PI: Miriam Zaťovičová. Duration: 2020-2023.

Collaboration projects:

Projects of The Ministry of Education, Science, Research and Sport of the Slovak Republic:

Research of humanized antibodies in targeted treatment of hypoxic tumors. Project code: (2018/14554:1-26C0), principal investigator: MABPRO a.s., PI: Jaromír Pastorek; Cooperating organization: BMC SAV, PI: Silvia Pastoreková. Duration: 2018-2021.

Projects of The Ministry of Health of the Slovak Republic:

Clinical evaluation of prognostic and predictive value of tissue and serum Carbonic Anhydrase IX in breast cancer. Project code: MZ SR 2019/26-LFUK-14. PI: Faculty of Medicine, Comenius University, Bratislava. PI: Kamil Pohlodek; Cooperating organization: BMC SAV, PI: Ingeborg Režuchová. Duration: 2019/2021.

European Union Structural Funds projects:

Integrative strategy in development of personalized medicine of selected malignant tumours and its impact on quality of life (LISPER). Project code: 313011V446, PI: Lekárska fakulta, UK BA, PI: Lukáš Plank; Cooperating organization: BMC SAV, PI: Miroslav Chovanec. Duration: 2019-2021.

Long-term strategic research of prevention, intervention and mechanisms of obesity and its comorbidities. Project code: NFP313010V344, PI: BMC SAV, PI: Silvia Pastoreková. Duration: 2020-2023.

Selected previous projects:

Biochips and biosensors for glycorecognition, their development, preparation and application in cancer research. Project code: APVV-14-0753. Coordinator: Institute of Chemistry, PI: Jaroslav Katrlík. Partner organization: Biomedical Research Center SAS, PI: Eliška Švastova. Duration: 2015-2019.

Role of the CA IX ectodomain in tumor growth and metastasis. Project code: Leona Lauder and George Schwab Foundation. PI: Silvia Pastoreková. Duration: 2014-2019.

Elucidation of novel pro-metastatic functions of hypoxia-induced carbonic anhydrase IX in pancreatic cancer. Slovak Academic Information Agency (SAIA)—Action Austria—Slovakia. Coordinator: BRC SAS, PI: Eliška Švastova. Host institution: Medical University of Vienna, Institute of Cancer Research, Supervisor: Paola Martinelli. Duration: 02/2018 – 07/2018.

Targeting carbonic anhydrase IX and pyruvate dehydrogenase kinase 1 in hypoxic colorectal tumors. Project code: SASPRO-0035/01/02, PI: Tereza Goliaš. Duration: 2015-2018.

Association of the hypoxia-induced carbonic anhydrase IX with drug response, miRNA profile and oncogenic pathways: from integrative analysis of the NCI60 cancer cell panel to cancer patients. Project code: SAS-MOST-JRP 2014/10. PI: Silvia Pastoreková. Duration: 2015-2017.

Biomedical engineering for cancer and brain disease diagnosis and therapy development. Project code: FP7-PEOPLE-2010-ITN-264417 (Project of the 7th Framework Program of the EU). Coordinator: Michiel J Vellekoop, Vienna University of Technology; Partner Organization: Institute of Virology, SAS, PI: Silvia Pastoreková. Duration: 2011-2015.

Metastatic tumour facilitated by hypoxic tumour microenvironments (METOXIA). Project code: HEALTH-2007-222741 (Project of the 7th Framework Program of the EU). Coordinator: Erik O. Pettersen, University of Oslo; Partner Organization: Institute of Virology, SAS, PI: Silvia Pastoreková. Duration: 2009-2014.

Hypoxia sensing, signalling and adaptation. Project code: COST Action TD0901. Coordinator: Roland Wenger, University of Zurich; Partner organization: Institute of Virology, SAS, PI: Silvia Pastoreková. Duration: 2009-2013.

RECENT

2020

2019

2017

2016

2015

MOST CITED

COLLABORATIVE PAPERS:

PATENTS

MN Gene and Protein, US patent 5,384,676 (inventori Závada, Pastoreková, Pastorek) a ďalšie rodiny medzinárodných patentov zameraných na diagnostické a terapeutické využitie nádorovo-asociovaného proteínu CA IX (pôvodne nazvaného MN),

Vrátane:

MN/CA9 splice variants (Pastorek, Baráthová)

MN/CA IX-specific monoclonal antibodies generated from MN/CA IX-deficient mice and methods of use (Pastorek, Pastoreková, Zaťovičová, Závada, Ortová-Gut, Závadová)

Soluble Form of Carbonic Anhydrase IX (s-CA IX), Assays to Detect s-CA IX, CA IXs Coexpression with HER-2/neu/c-erbB-2 and CA IX-Specific Monoclonal Antibodies to Non-Immunodominant Epitopes (Pastorek, Pastoreková, Zaťovičová, Závada, Ortová-Gut, Závadová)