Insight into Intratumoral Heterogeneity Through Single CTC Sequencing and CDX Analysis

Tumors contain a high degree of molecular heterogeneity which is the substrate of therapeutic resistance and is rooted both by genomic instability and by phenotypic plasticity. Hematogenous dissemination of circulating tumor cells (CTCs) is considered as the major form of metastatic spread to distant organs. Genomic and functional characterization of CTCs may provide insight into the biology of cancer cells that promote metastases formation and provide a route to disease progression. As CTCs integrate information from spatially distinct metastatic sites, they may inform intratumoral heterogeneity and therapeutic resistance mechanisms. Here, we show how CTC analyses at the single-cell level may provide important information regarding intratumoral heterogeneity and potential therapeutic resistance mechanisms in ALK-positive non-small-cell lung cancer (NSCLC). We also present the phenotypical and genetic characterization of a neuroendocrine trans-differentiation castration-resistant prostate cancer (CRPC) CTC-derived xenograft (CDX) model. This CDX model represents a unique tool to improve our understanding of lineage plasticity and genetic mechanisms driving therapeutic resistance in CRPC.