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Obtained: Ligue contre le Cancer/Région Bretagne
Sheet abstract of thesis 2017
Disciplinary Fields Santé et Autres
Thesis Title : (1-2 lines)
Epigenetic of lymphoid stroma : model of Follicular Lymphoma
3 keywords : (1 line)
Epigenetic/ lymphoid stroma / oncology
ACRONYME
EPISTROMA
Unit/Team of supervising : (1-2 lines)
UMR 1236 MICMAC
Name of the scientific director and co-director : (1 line)
Pr. TARTE Karin and Dr. Roulois David (co-director)
Contact : (1 line)
[email protected] , [email protected]
Socio-economic and scientific context: (10 lines)
Follicular lymphoma (FL) is the second most diagnosed lymphoma in Caucasian population and the most frequent of
indolent lymphomas. FL is a pertinent model for the study of the co-evolution between tumor and supportive
microenvironment. This microenvironment comprises lymphoid stromal cells that correspond to the cancerassociated fibroblasts (CAF) found in solid tumor. Nowadays, the FL niche is mostly studied by phenotypic,
transcriptomic and functional approaches but not by epigenetic approaches yet involve in cell differentiation
mechanisms. A better understanding of the regulation mechanisms of these niche is necessary especially since FL is
still an incurable disease with tumor relapse after treatment associated with the interaction of FL B cells with a
supportive microenvironment.
Assumptions and questions (8 lines)
In this project, we hypothesis that epigenetics mechanisms are involves in normal and tumor lymphoid stromal
differentiation. We will study importance of these mechanisms in setting up normal lymphoid stroma and will
determine whether theses mechanisms are identical or deregulated in tumor lymphoid stroma/ FL-CAF and which
are their role in the supportive properties of FL-CAF toward growth and cell survival of FL B cells. In a second step,
we will determine whether is it possible to block the emergence of tumor lymphoid stroma by the use of epigenetic
inhibitors and especially ask impact of inhibitors use to target cancers cells on physiological and tumor lymphoid
stroma.
The main steps of the thesis and demarche (10-12 lines)
In order to carry out these objectives, two approaches will be developed:
-A targeted approach were will we focus on a target identify in laboratory: the JMJD3 protein. Indeed, preliminary
results and data from literature, suggest a possible role for the KDM6B/JMJD3 protein (an H3K27me3/2
demethylase) in lymphoid stromal cells differentiation process. We will validate the role and importance of this
protein in setting up a tumor lymphoid stroma, as well as in its functions to sustain FL B cell survival and
proliferation.
-A global approach, were will we defined an epigenetic signature of lymphoid stromal cells (progenitor and
differentiated cells) as well as tumor lymphoid stromal cells by the study of the open chromatin landscape by ATACseq. By these study, we will research new candidates targets. Importance of these candidates will then be validated
by a functional analysis (importance for phenotype and function of the tumor lymphoid stroma).
Methodological and technical approaches considered (4-6 lines)
In this project different technics will be used.
Cellular approaches were technics of cell culture, flow cytometry (phenotype and cell sorting), lentivirus carrying
shRNA, and confocal microscopie will be used.
A molecular approaches were technics of q-PCR, ChIP, ATAC-seq, RNA-seq and western blot will be used
In addition, Bio-informatics analysis and animal model approach will be need to this project.
Scientific and technical skills required by the candidate (2 lines)
Solid knowledge in immunology and oncology
Skill in molecular and cell biology, and interest for bio-informatics approaches