A new report delineates how the primary tumor stroma may preselect breast cancer cells that have specific metastatic tropism for bone (Cell 154, 1060–1073).

Credit: James Cavallini / Science Source

Breast cancers are prone to metastasizing to bone, among other organs. Now, Xiang Zhang et al. show that interactions between cancer cells and the primary tumor stroma may enrich for tumor cells better fitted to survive and colonize specific tissues such as bone.

Previous research had shown that activation of SRC signaling in primary breast tumors, independent of their subtype, correlates with bone metastasis. In this report, the authors focused on a subset of triple-negative breast tumors, which show metastatic tropism for bone and in which SRC activation is not linked to a driver oncogenic event.

The authors studied how cells that have activated SRC signaling are enriched in some primary tumors prior to metastatic spread, and they found that signals from the breast stroma can exert a positive selection for this trait. Cancer-associated fibroblasts (CAFs) were enriched in the environment of bone-tropic triple-negative breast tumors, where they secreted the factors C-X-C motif chemokine 12 and insulin-like growth factor 1. SRC activation enhances the effects of these cytokines on downstream signaling pathways that promote survival and growth of tumor cells. Interestingly, the researchers found that these cytokines are also enriched in the bone marrow stroma of triple-negative tumors. The cytokine-secreting CAFs in the primary tumor stroma can confer a growth advantage to cells with activated SRC signaling from the tumor milieu that primes them for survival and growth in the secondary bone environment.

The findings add a layer of complexity to the exquisite regulation of metastatic organotropism and shed light on how it can be selected for before spread occurs, further paving the way for potential therapeutic interventions early in metastasis.