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Dr. Erika Brunet - CRISPR/Cas9 functional models of cancer translocations: from molecular mechanisms to oncogenesis

 

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Erika Brunet

Genome dynamics in the immune system, Institut IMAGINE, Paris

 

CRISPR/Cas9 functional models of cancer translocations: from molecular mechanisms to oncogenesis

Chromosomal translocation are hallmarks of cancers. The main challenge has been to achieve functional modeling of cancers associated with translocation from primary cells. Using CRISPR/Cas9 system, we now manage to model different cancers associated translocation in the relevant human primary cells, enabling us to reproduce the stochastic nature of the formation of tumors that develop from a single cell in human. We focused on 2 different cancer models: Anaplasic Large Cell Lymphoma (ALK+) and Ewing Sarcoma. Our studies aim to explore precisely the mechanistic process leading to the overall structural changes that can induce diverse modifications of the chromatin structure and/or the nuclear organization of the cell after translocation formation (including replication timing, epigenetic, transcriptome modification, non-coding RNA expression...). Meanwhile, we also pursue to understand the underlying biology of ALCL(ALK+) and Ewing sarcoma tumorigenesis, by deciphering the cellular transformation process resulting from translocation formation in a step by step approach (in vitro but also in vivo).

Selected references

  • Babin et al. 2018 Chromosomal translocation formation is sufficient to produce fusion circular RNAs specific to patient tumor cells. iScience 5:19-29
  • Brunet et al. 2018 Induction of chromosomal translocations with CRISPR-Cas9 and other nucleases: Understanding the repair mechanisms that give rise to translocations. Adv Exp Med Biol 1044:15-25
  • Phillips et al. 2017 Single-molecule analysis of mtDNA replication uncovers the basis of the common deletion. Mol Cell 65(3):527-538.e6
  • Ghezraoui et al. 2014 Chromosomal translocations in human cells are generated by canonical nonhomologous end-joining. Mol Cell 55(6):829-842
  • Simsek et al. 2011 DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation. PLOS Genet 7(6):e1002080
  • Brunet et al. 2009 Chromosomal translocations induced at specified loci in human stem cells. Proc Natl Acad Sci USA 106(26):10620-5
  • Weinstock et al. 2007 Formation of NHEJ-derived reciprocal chromosomal translocations does not require Ku70. Nat Cell Biol 9(8):978-81

 

Contact: Florence Larminat (florence.larminat@ipbs.fr)

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8 Oct

11:00 - 12:00

Fernand Gallais Conference room