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SUMMARY:Towards unification of genetic and hierarchy models of tumor heter
 ogeneity - John Dick\, University of Toronto
DTSTART:20120404T120000Z
DTEND:20120404T130000Z
UID:TALK32824@talks.cam.ac.uk
CONTACT:Kate Davenport
DESCRIPTION:The cellular and molecular basis for intra-tumoral heterogenei
 ty is poorly understood. Tumor cells can be genetically diverse due to mut
 ations and clonal evolution resulting in intra-tumoral functional heteroge
 neity. Often proposed as mutually exclusive\, cancer stem cell (CSC) model
 s postulate that tumors are cellular hierarchies sustained by CSC heteroge
 neity due to epigenetic differences (i.e. long term tumor propagation only
  derives from CSC). The clinical relevance of CSC has been challenged by r
 ecent reports that some tumours may actually not adhere to a CSC model whe
 n the xenograft system is enhanced. Two lines of evidence support the CSC 
 model in AML and B-ALL. We have recently developed gene signatures specifi
 c to either AML LSC or normal HSC and found they share a set of genes that
  define a common stemness program. Only these stem cell related gene signa
 tures were found to be highly significant independent predictors of patien
 t survival when large clinical databases were introgated. Thus\, determina
 nts of stemness influence clinical outcome of AML establishing that LSC ar
 e clinically relevant and not artifacts of xenotransplantation. Second\, w
 e have carried out a series of combined genetic and functional studies of 
 Ph+ B-ALL leukemic initiating cells (L-IC) that point to commonalities bet
 ween clonal evolution and CSC models of cancer. L-IC from diagnostic patie
 nt samples were genetically diverse and reconstruction of their genetic an
 cestry showed that multiple L-IC subclones were related through a complex 
 evolutionary process that involved both linear or branching leukemic progr
 ession. The discovery that specific genetic events influence L-IC frequenc
 y and that genetically distinct L-IC evolve through a complex evolutionary
  process indicates that a close connection must exist between genetic and 
 functional heterogeneity. Finally\, our study points to the need to develo
 p effective therapies to eradicate all genetic subclones in order to preve
 nt further evolution and recurrence.
LOCATION:Cancer Research UK Cambridge Research Institute\, Lecture Theatre
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