The bone microenvironment induced metastatic cancer cells to further disseminate to other organs.

  • Major Finding: The bone microenvironment induced metastatic cancer cells to further disseminate to other organs.

  • Concept: The bone microenvironment enhanced secondary metastasis via EZH2-mediated epigenetic reprogramming.

  • Impact: This work shows that the bone-metastatic niche can play a key role in seeding secondary metastases.


Metastasis of cancer cells from primary tumors to secondary sites accounts for the majority of cancer-related deaths, and recent work has suggested that existing metastases can seed secondary metastases. Because bone is not only the most common but also often the first site of breast cancer metastasis, Zhang, Bado, and colleagues developed a preclinical model to investigate mechanisms that may underpin metastatic dissemination from bone lesions. When human breast cancer cells were injected into mice via the intrailiac artery, tumors first formed in bone at early timepoints, followed by the establishment of metastatic lesions in distant organs after several weeks. When compared with injections via the intrailiac vein or orthotopic injections into the mammary fat pad, intrailiac artery injections resulted in more rapid and widespread secondary metastases, suggesting that the bone microenvironment to which cancer cells are exposed following intrailiac artery injection enhanced the metastatic phenotype. A parabiosis model involving the fusion of circulation between a bone lesion–carrying donor mouse and a tumor-free recipient showed that, although shared circulation was not enough for efficient metastatic dissemination, bone lesions still seeded secondary metastases in the recipient whereas mammary fat pad lesions did not. To analyze phylogenetic relationships between bone lesions and subsequently formed metastases, an evolving barcode system was used that revealed parent–child relationships between primary and secondary metastases, showing that metastases could seed other metastases. Importantly, the dissemination was able to occur from small lesions. When single cell–derived progeny of human breast cancer cells were injected into various organs to form tumors and extracted from mice after several weeks, bone-entrained cancer cells were more metastatic than mammary fat pad– or lung-entrained cancer cells, showed reduced organotropism, and displayed ALDH1 activity and CD44 expression, two markers of stemness. These bone-entrained phenotypes were reversible, indicating a mechanism independent of genetic selection. Bone-entrained cancer cells exhibited high EZH2 activity, and pharmacologic or genetic inhibition of EZH2 significantly reduced secondary metastases. In summary, this work reveals that the bone microenvironment, through EZH2-mediated reprogramming, enhances further spread of metastases to multiple organs.

Zhang W, Bado IL, Hu J, Wan Y-W, Wu L, Wang H, et al. The bone microenvironment invigorates metastatic seeds for further dissemination. Cell 2021;184:2471–86.E20.

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