Findings from Ola Myklebost's group published in Cancer

Myklebost and Kresse
Myklebost and Kresse
As members of the European Network of Excellence Eurobonet, the group of Ola Myklebost has assembled and characterised in detail a large collection of preclinical models of sarcoma, malignant tumours of connective tissue. In a recent study published in Cancer, the journal of the American Cancer Society, with Stine Kresse and Ola Myklebost (photo) as first and last author - they used array-based comparative genomic hybridisation (arrayCGH) employing in-house arrays to compare in great detail to what extent a panel of sarcoma xenografts - human tumour samples propagated by serial transplantation in immune-deficient mice - are identical to their tumour of origin, and whether there are systematic changes that occur during passaging in mice.

This is the most extensive such study to date, and showed that although the detailed patterns of genomic aberrations are very similar between the donor samples and early transplants, clear differences can be observed. However, these are scattered all over the genome, and most likely are due to the heterogeneity in the donor tissues. Interestingly, in most cases the changes were towards more normal genomes, i.e. loss of aberrations, possibly due to reduced cellular heterogeneity caused by clonal simplification.

On the other hand, when changes that occur during serial transplantation in mice were scored, some significantly recurrent changes were observed, all in osteosarcomas, which are known for their high genomic instability. Aberrations that increased were of the same type as observed also in patient samples, and most likely were due to normal tumour progression. On the other hand, aberrations that disappeared contained genes that may be involved in chemotherapy response and immune evasion, and it seems likely that these could have appeared due to selection in the patient by chemotherapy and the immune response to the tumour, and were lost because these selection pressures were no longer present in the mice.

In conclusion, the xenografts are good preclinical models, resembling their tumours of origin well. The fluctuation of copy number aberrations reflects the natural heterogeneity in tumours, and thus may not be a significant disadvantage. The study also confirms the well-known caveats when using models in immune-deficient mice for studies of cancer-stroma interactions and immune-related mechanisms.

The figure shows the chromosomal copy number profiles for an osteosarcoma patient sample (black), the tumour that grew on implantation in mice (blue), passage 5
The figure shows the chromosomal copy number profiles for an osteosarcoma patient sample (black), the tumour that grew on implantation in mice (blue), passage 5


Links

Preclinical xenograft models of human sarcoma show nonrandom loss of aberrations.
Kresse SH, Meza-Zepeda LA, Machado I, Llombart-Bosch A, Myklebost O.
Cancer. 2011

European Network of Excellence Eurobonet

Cancer (journal published on behalf of the American Cancer Society)

Home page of Ola Myklebost's group

Ola Myklebost's CV and publications

Department of Tumor Biology

Institute for Cancer Research

 
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