Lymphatic system is the mainstream for breast cancer dissemination and metastasis revealed by single-cell lineage tracing

Cancer metastasis is responsible for majority of cancer related death, yet the forces that drive cancer cells through various steps and different routes to distinct target organs/tissues remain elusive. In this study, we applied the Celltag system based single-cell lineage tracing approach to illustrate the rate and route of breast cancer cells, and their interactions with tumor microenvironment (TME) during metastasis. The results indicate that only small fraction of cells could evacuate from the primary site into the blood circulation whereas more cells go through the lymph system to different organs. Tumor cells of same ancestor exhibit different gene expression pattern in different circumstances, and communication paradigm of cancer cell-TME varies significantly between primary tumor and metastatic tumors. Furthermore, metastable cells require pre-wired with Il2 secretion ability to achieve the in vivo migration ability. Overall, with the help of single-cell lineage tracing system, we demonstrate the crosstalk between tumor cells and TME is the driving force to engage the metastasis fate of cancer cells mainly through the lymphatic route, which can be suppressed by knockdown of IL2.