Abstract
Injection of DNA-barcoded cancer cell lines into mice revealed their metastatic characteristics.
Major Finding: Injection of DNA-barcoded cancer cell lines into mice revealed their metastatic characteristics.
Concept: Organ-specific metastatic potential depended on factors such as genomic features of cell lines.
Impact: This proof-of-concept study shows that characteristics driving metastasis can be readily determined.
Mouse xenograft models can be used to evaluate the metastatic potential of human cancer cell lines in vivo, but large-scale studies defining the metastatic characteristics of cancer cell lines are impractical. Jin and colleagues developed a barcoding strategy in which 500 cell lines representing 21 solid tumor types were each engineered to express a unique 26-nucleotide barcode. This enabled the cell lines to be pooled and injected into immunodeficient mice, where they were grown for five weeks to allow for metastatic seeding and for the cell line of origin of each metastatic lesion to be determined using barcode quantification via sequencing. In a complementary experiment, five pools of 125 cell lines each were injected into individual mice. By comparing the proportion of a given barcoded cell line in metastatic lesions with the proportion of that cell line preinjection, the metastatic potential of the cell lines toward individual organs was determined. As expected, cell lines derived from metastatic tumors exhibited greater metastatic potential on average than cell lines derived from primary tumors, and cell lines from tumors generally considered to have high metastatic potential (e.g., melanoma and pancreatic cancer) had higher metastatic propensities. However, cell proliferation rate and mutation burden were not strongly predictive of metastatic potential. Focusing on the potential of basal breast cancer cells to spawn brain metastases, it was revealed that four of seven brain-metastatic breast cancer cell lines harbored PIK3CA mutations, whereas such mutations were found in none of the 14 nonmetastatic or weakly metastatic breast cancer cell lines. There was also an association between brain metastasis and deletions of chromosome 8p12–8p21.2, with five of seven metastatic lines harboring such deletions and none of the 14 nonmetastatic or weakly metastatic lines harboring such deletions. Interestingly, brain-metastatic breast cancer cells had aberrant lipid metabolism, and altering this lipid metabolism hindered metastasis. Collectively, these findings support the use of metastasis mapping as a platform for new discoveries.
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