Abstract
Cancer cells varied in metastatic potential before xenotransplantation; these differences were heritable.
Major Finding: Cancer cells varied in metastatic potential before xenotransplantation; these differences were heritable.
Concept: Complex routes were taken by metastatic cells, with backtracking to the original organ being possible.
Impact: This work provides insight into metastasis and highlights the power of new lineage tracing methods.
Lineage tracing analyses have enabled the gain of insights into metastatic processes, but most existing methods suffer from several limitations, including, for example, low resolution or inability to distinguish directionality of metastatic spread. To circumvent these issues, Quinn, Jones, and colleagues used a Cas9-based lineage tracing technique that employs single-cell RNA sequencing to determine cancer phylogenetic trees at subclonal resolution, revealing previously unknown features of metastasis. Use of this system in a mouse xenograft model of highly metastatic KRAS-mutant lung adenocarcinoma enabled the reconstruction of high-resolution phylogenetic trees that depicted the phylogenetic relationships among cells within each clonal population along with the cells' metastatic trajectories from tissue to tissue. Analysis of the constructed phylogenetic trees revealed that cells vary in their propensity to seed metastases (i.e., they have low, moderate, or high metastatic potential) independently of clonal population size, proliferation rate, or cell cycle stage; this variation in metastatic potential was observed not only between clonal populations but also within them. Differences in metastatic potential were correlated with transcriptomic differences, with one noticeable anticorrelation appearing between metastatic potential and expression of KRT17, encoding a keratin. In seeming contradiction, KRT17 expression had previously been associated with promotion of lung adenocarcinoma invasiveness and poor prognosis among some other cancers, but transwell migration assays to test for invasiveness in vitro also indicated a proinvasive role for KRT17 expression in multiple lung cancer cell lines. Additionally, in vivo experiments showed that the transcriptomic signatures of cells with low, moderate, or high metastatic potential were already present in the cancer cells prior to implantation into mice, and further investigation showed that these differences in metastatic potential and the associated transcriptomic profiles were usually stably inherited, although evolution from one state to another was observed to be possible. A final analysis revealed that metastatic cells took complex routes from location to location, sometimes backtracking or even transiting back to the location of origin, highlighting how this lineage tracing method can reveal intricate details of metastasis.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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