Eradication of advanced disease remains elusive in the majority of cancers including soft tissue sarcomas (STS) despite advances in our understanding of the molecular mechanisms that drive them. Targeted treatment development to date has largely relied upon data derived from all cells within a tumour sample and/or tumour cell lines. These approaches however, do not account for inherent heterogeneity of cancer cells within a single tumour and is considered an important factor that leads to treatment failure. Understanding intra-tumour heterogeneity is therefore a priority for cancer research and appropriate tumour models with sufficient availability would greatly facilitate the identification of newer targets and factors that lead to treatment resistance. We therefore aimed to develop in vitro models of STS that reflect intra-tumour heterogeneity.
We obtained tissue from patients having surgery for STS in Sheffield Teaching Hospitals and established primary tissue cultures. Short Tandem Repeat (STR) confirmed the same origin of both clones in both cases. DNA copy number profiling and gene expression microarray analysis were used for molecular characterisation of self-immortalised primary cell lines.
One leiomyosarcoma (Shef-LMS 01) and one myxofibrosarcoma cell line (Shef-MFS 01) established two morphologically-distinct tumour cell types (culture variants) in separate long term cultures. Karyotyping and growth characteristics confirm that both variants in each case are tumour cells and they have remained in culture for over 100 passages. STR profiling confirms that in each case, both clones are derived from the same tumour. DNA copy number analysis with microarray-based comparative genomic hybridisation and gene expressson analysis shows many identical somatic copy number abnormalities (SCNA) between variants, but also numerous genomic and transcriptomic differences.
We believe that these genomic and transcriptomic differences provide clues to clonal evolution in these tumours and may explain the development of resistance to targeted treatment. These cell lines are therefore useful for the identification of novel targets and development of effective therapies for these tumours.
Clinical trial identification
Legal entity responsible for the study
Weston Park Cancer Charity and Sarcoma UK
All authors have declared no conflicts of interest.