Abstract
The most common site of breast cancer metastasis is the bone, occurring in approximately 70% of patients with advanced disease. Bone metastasis is associated with severe morbidities and high mortality. Therefore, deeper understanding of the mechanisms that enable bone-metastatic relapse are urgently needed. We report the establishment and characterization of a bone-seeking variant of breast cancer cells that spontaneously forms aggressive bone metastases following surgical resection of primary tumor. We characterized the modifications in the immune milieu during early and late stages of metastatic relapse and found that the formation of bone metastases is associated with systemic changes, as well as modifications of the bone microenvironment towards an immune suppressive milieu. Furthermore, we characterized the intrinsic changes in breast cancer cells that facilitate bone-tropism and found that they acquire mesenchymal and osteomimetic features. This model provides a clinically relevant platform to study the functional interactions between breast cancer cells and the bone microenvironment, in an effort to identify novel targets for intervention.
Highlights
The most common site of breast cancer metastasis is the bone, occurring in approximately 70% of patients with advanced disease
In order to enable investigation of the metastatic microenvironment in spontaneous bone metastases, we generated a bone seeking variant of the murine triple negative breast cancer cell line 4T1 by in vivo passaging in immune competent syngeneic mice, as previously d escribed33. 4T1 cells were orthotopically inoculated to the fourth mammary gland of 6 weeks old BALB/c female mice
We compared the aggressiveness of the different clones by analyzing the survival of injected mice after removal of the primary tumors, and found that mice injected with the bone-metastasizing clones had significantly reduced survival as compared with the parental cell line (Fig. 1D)
Summary
The most common site of breast cancer metastasis is the bone, occurring in approximately 70% of patients with advanced disease. We report the establishment and characterization of a breast cancer bone-metastasizing cell line following surgical removal of the primary tumor. In order to enable investigation of the metastatic microenvironment in spontaneous bone metastases, we generated a bone seeking variant of the murine triple negative breast cancer cell line 4T1 by in vivo passaging in immune competent syngeneic mice, as previously d escribed[33].
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