TY - JOUR
T1 - Isogenic Cell Lines Derived from Specific Organ Metastases Exhibit Divergent Cytogenomic Aberrations
AU - Winnard, Paul T.
AU - Morsberger, Laura
AU - Yonescu, Raluca
AU - Jiang, Liqun
AU - Zou, Ying S.
AU - Raman, Venu
N1 - Funding Information:
Venu Raman acknowledges support from National Institute of Health grant number 1R01CA207208.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
KW - comparisons
KW - inter- and intra-cytogenomic heterogeneity
KW - isogenic metastatic cell lines
KW - karyotypes
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U2 - 10.3390/cancers15051420
DO - 10.3390/cancers15051420
M3 - Article
C2 - 36900209
AN - SCOPUS:85149780776
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 5
M1 - 1420
ER -