Share
Lymphoid microenvironment models and their use to study targeted therapy and resistance in B cell malignancies
Doctoral study program
Life Sciences (Faculty of Science, Masaryk University)
Supervisor
Prof. Marek Mraz, MSc., M.D., Ph.D.
Consultant
Annotation
Chronic lymphocytic leukemia (CLL) cells and indolent lymphomas are known to be dependent on diverse microenvironmental stimuli providing them signals for survival, development, proliferation, and therapy resistance. It is known that CLL cells undergo apoptosis after cultivation in vitro, and therefore it is necessary to use models of CLL microenvironment to culture CLL cells long-term and/or to study their proliferation. Several in vitro and in vivo models meet some of the characteristics of the natural microenvironment based on coculture of malignant cells with T-lymphocytes or stromal cell lines as supportive cell, but they also have specific limitations.
The aim of this research is to develop and use models mimicking lymphoid microenvironment to study novel therapeutic options, e.g. drugs targeting CLL proliferation, development of resistance in long-term culture or combinatory approaches, which cannot be analysed in experiments based on conventional culture of CLL/lymphoma primary cells. This project will utilize models developed in the laboratory and will further optimize and modify them. We have recently developed a co-culture model that is allowing to induce robust proliferation of primary CLL cells, something that was virtually impossible for decades (Hoferkova et al, Leukemia, 2024). Using kinase inhibitors, the biology of CLL and responses to targeted treatment will be interrogated. The student will utilize various functional assays, RNA sequencing, genome editing, drug screening etc., with the use of primary patient’s samples and cell lines. The research might bring new insights into the microenvironmental dependencies and development of resistance to targeted therapy.
Recommended literature
- Hoferkova E, et al…. Mraz M. Stromal cells engineered to express T cell factors induce robust CLL cell proliferation in vitro and in PDX co-transplantations allowing the identification of RAF inhibitors as anti-proliferative drugs. Leukemia. 2024 Aug;38(8):1699-1711
- Pavlasova G, et al…. Mraz M. Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis. Blood. 2016 Sep 22;128(12):1609-13. doi: 10.1182/blood-2016-04-709519. Epub 2016 Aug 1. PMID: 27480113 Free PMC article
- Kipps et al. Chronic lymphocytic leukaemia. Nat Rev 2017 https://pubmed.ncbi.nlm.nih.gov/28102226/
- Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol. 2015 Mar;94(3):193-205. doi: 10.1111/ejh.12427. Epub 2014 Sep 13. PMID: 25080849 Review.
Research area
Cancer biology
Keywords
lymphoma, CLL, migration, microenvironment, co-culture
Funding for the PhD candidate
Part-time salary (min. 0,5 FTE) on EHA grant/AZV/GACR grants + national scholarship (equals approx. half-time salary); guaranteed net income after taxes of min. 25.000 CZK
Requirements on candidates
- Motivated smart people that have the “drive” to work independently, but also willing to learn from other people in the lab and collaborate.
- Candidates should have a master’s degree in Molecular biology, Biochemistry, or similar field and have deep interest in molecular biology and cancer cell biology.
Information about the supervisor
H-index 30 (citations > 3500, 50 publications with IF), currently principal investigator of 4 grants (AZV 3x, NPO, in the past ERC Starting grant). Dr. Mraz has currently 7 PhD students, with 3 finishing soon). international collaborations: University of Southampton, Univ.California- San Diego, Mayo Clinic, Dana-Farber Cancer Institute, EMBL, University of Turin (student internship available), member of EHA Comittee, reviewer in scientific journals: Blood, Leukemia, Leukemia Research; https://is.muni.cz/auth/osoba/101627;
More information about the research group: http://mrazlab.ceitec.cz/