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CATEGORIES:Cambridge Oncology Seminar Series
SUMMARY:‘Cellular Plasticity in Cancer:  driving force and
  therapeutic target’ - Professor Thomas Brabletz\,
  Department of Experimental Medicine\, University 
 Erlangen-Nuernberg
DTSTART;TZID=Europe/London:20180605T110000
DTEND;TZID=Europe/London:20180605T120000
UID:TALK105442AThttp://talks.cam.ac.uk
URL:http://talks.cam.ac.uk/talk/index/105442
DESCRIPTION:*Abstract*:\n\nWe have shown\, that in particular 
 tumor cells at the invasive front undergo a partia
 l epithelial-mesenchymal transition (EMT) and aber
 rantly express EMT-associated transcription factor
 s (EMT-TFs). The amount of such cancer cells stron
 gly correlates with metastasis formation and poor 
 clinical outcome in human cancers. Strikingly\, me
 tastases show a mesenchymal-epithelial re-transiti
 on (MET) with a re-differentiated phenotype\, indi
 cating high cancer cell plasticity and supporting 
 a regulatory role of the tumor environment. We des
 cribed that the EMT-TF ZEB1 is a crucial determina
 nt of cellular plasticity. At molecular level\, ZE
 B1 is linked in a double negative feedback loop wi
 th the miR-200 family and miR-203\, which are stro
 ng inducers of epithelial differentiation. Thus ab
 errant ZEB1 expression stabilizes EMT and stemness
 \, thereby promoting dissemination\, metastasis an
 d drug resistance of cancer cells. We have validat
 ed the findings\, by showing that a depletion of Z
 EB1 in the KPC-mouse model of pancreatic cancer co
 unteracts tumor cell plasticity and metastasis. Mo
 reover we detected that ZEB1 controls the Notch pa
 thway and directly cooperates with the Hippo-pathw
 ay effector YAP in driving aggressive cancer types
 . We determined epigenetic modifications conferred
  by ZEB1\, screened for epigenetic drug to restore
  expression of its silenced target genes and to su
 bsequently overcome therapy resistance. Despite th
 eir potent tumor-promoting effects\, EMT-TFs are r
 arely mutated in cancer. This likely due to the ne
 cessity for a transient expression and the associa
 ted plasticity of cancer cells\, underscoring the 
 important role of non-mutated genes in cancer prog
 ression. \n\n
LOCATION:Sackler Lecture Theatre (Level 7)\, Cambridge Inst
 itute for Medical Research
CONTACT:Mala Jayasundera
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