SUMMARY Metastasis has been considered as the terminal step of tumor progression. However, recent clinical studies suggest that many metastases are seeded from other metastases, rather than primary tumors. Thus, some metastases can further spread, but the corresponding pre-clinical models are lacking. By using several approaches including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. Importantly, dissemination from the bone microenvironment appears to be more aggressive compared to that from mammary tumors and lung metastases. We further uncovered that this metastasis-promoting effect is independent from genetic selection, as single cell-derived cancer cell populations (SCPs) exhibited enhanced metastasis capacity after being extracted from the bone microenvironment. Taken together, our work revealed a previously unappreciated effect of the bone microenvironment on metastasis evolution, and suggested a stable reprogramming process that engenders cancer cells more metastatic.

The bone microenvironment invigorates metastatic seeds for further dissemination