Thursday, October 9, 2014

Clone wars

7:51 AM Posted by sandmann , , No comments
At the Tumor Heterogeneity: Implications for Targeted Therapy conference in Stanford on October 6th, 2014, Kornelia Polyak (Harvard Medical School) described how her lab used fluorescence in situ hybridization (iFISH) and allele-specific PCR-FISH (STAR-FISH) to image copy number variation and point-mutations of breast cancer at the single-cell level. She highlighted how treatment with anti-HER2 antibodies induced changes in the composition of tumors in a breast cancer cohort, including a  post-treatment enrichment of PI3K mutant cells.

 
To understand how clonal heterogeneity is maintained over time and study the role of interactions between clones, her lab performed xenograft experiments with combinations of cell lines engineered to over-express different non-cell autonomous drivers. Polyclonal tumors, containing a mixture of cell lines, grew faster than clonal xenografts and produced metastases earlier.

Among many other findings, the researchers found that IL11 expression by even a small number of cells in the xenograft increased its density of blood vessels. This promoted growth of the tumor as a whole, including that of the other sub-clones, providing direct experimental evidence for interactions between clonal sub-populations.

As pointed out during the lively discussion, these experiments focused on selected secreted signaling molecules and did not investigate the competitiveness of well-known driver oncogenes such as e.g. mutant KRAS. (KRAS mutant cell lines grew too fast to be included in the xenograft experiment.)

References:

Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity; Marusyk et al, Nature, 2014

0 comments:

Post a Comment