A complex seeding of multiple metastases in clear cell renal cell carcinoma (CGH)

Tumor heterogeneity resulting from clonal evolution is a frequent feature in clear cell renal cell carcinoma (ccRCC) and could play a role in metastatic dissemination. However, the dynamics of metastatic evolution is not completely elucidated and could follow a complex seeding process. Using a unique experimental design with a rare matched primary-metastatic case prior to any medical treatment, we retraced the lineage of metastatic clones that showed a complex, multiple, polyphyletic seeding of two functionally interdependent subclonal populations originating from the primary tumor, in the direction of all metastatic sites. We used integrative omics approaches combining genomic and transcriptomic data, on fourteen specimens from different macroscopic areas of a primary kidney tumor and three non-primitive sites including a vein thrombus and two metastases. All sites were heterogeneous and polyclonal, each containing simultaneously two aggressive sub clonal populations, with differentially expressed genes implicated in distinct biological functions. Our hypothesis is a polyclonal seeding with interactions between each sub-population in every analyzed metastatic context. Multiple interdependent lineages could be the source of metastatic heterogeneity in ccRCC and could affect clinical outcome. Combining similar sampling strategies with single-cell transcriptomic approaches would produce a clearer picture of the subclonal evolution in ccRCC.