Isogenic Cell Lines Derived from Specific Organ Metastases Exhibit Divergent Cytogenomic Aberrations

SIMPLE SUMMARY: Normal human cells have 22 pairs of chromosomes as well as 2 sex chromosomes for a total of 46 chromosomes; this normal karyotype is called diploidy (euploidy). On the other hand, aberrant numbers of chromosomes, i.e., gains and/or losses of chromosomes, have been found in most human cancer cells. This condition is called aneuploidy. Within in a clinical context, aneuploidy has been shown to be a marker of poor prognosis and drug resistance. Importantly, the deadliest stage of a cancer occurs when the cancer has been found to have spread from a primary tumor site to other organ sites, which is called metastasis. Controlled comprehensive clinical studies of metastatic cancer, which require an interrogation of the affected site(s), such as lungs, or liver, brain, or bone, with the goal of developing better treatment are very challenging. Therefore, repeatable controlled studies of complex human metastatic disease are simulated in animal systems using human cancer cells in special mouse strains. We used such a model system to better understand the chromosomal changes and the processes that bring them about, along with a study of gene variants, chromosomal amplifications, gains, and losses in metastatic cancer cells. We compared these differences to their primary tumor cell counterparts. This information aids us in suggesting possible new therapeutic treatments that may have a potential to limit the growth of metastatic cancer. ABSTRACT: Aneuploidy, a deviation in chromosome numbers from the normal diploid set, is now recognized as a fundamental characteristic of all cancer types and is found in 70–90% of all solid tumors. The majority of aneuploidies are generated by chromosomal instability (CIN). CIN/aneuploidy is an independent prognostic marker of cancer survival and is a cause of drug resistance. Hence, ongoing research has been directed towards the development of therapeutics aimed at targeting CIN/aneuploidy. However, there are relatively limited reports on the evolution of CIN/aneuploidies within or across metastatic lesions. In this work, we built on our previous studies using a human xenograft model system of metastatic disease in mice that is based on isogenic cell lines derived from the primary tumor and specific metastatic organs (brain, liver, lung, and spine). As such, these studies were aimed at exploring distinctions and commonalities between the karyotypes; biological processes that have been implicated in CIN; single-nucleotide polymorphisms (SNPs); losses, gains, and amplifications of chromosomal regions; and gene mutation variants across these cell lines. Substantial amounts of inter- and intra-heterogeneity were found across karyotypes, along with distinctions between SNP frequencies across each chromosome of each metastatic cell line relative the primary tumor cell line. There were disconnects between chromosomal gains or amplifications and protein levels of the genes in those regions. However, commonalities across all cell lines provide opportunities to select biological processes as druggable targets that could have efficacy against the primary tumor, as well as metastases.