CHEMOTHERAPY-INDUCED STROMAL REMODELING: IMPLICATIONS FOR BONE MATRIX MINERALIZATION AND TUMOR GROWTH
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Bone is a common site for breast cancer metastasis and relapse. However, it remains poorly understood how chemotherapeutic drugs used to treat primary breast cancer affect bone remodeling and which effect these changes have on metastatic outgrowth. Understanding these connections is critical as doxorubicin (dox) can impair bone formation, an emerging key risk factor for the development of bone metastases. Previous studies have shown that dox disrupts soluble factor signaling between bone marrow-derived mesenchymal stem cells (MSCs) and tumor cells, notably increasing pro-inflammatory cytokines. Despite these findings, the mechanisms by which dox affect bone matrix formation and mineralization by MSCs; and how these changes influence tumor progression remain unclear, partly due to a lack of physiologically relevant models for studying these processes under in-vivo-like conditions. Here, I hypothesize that dox disrupts MSC-dependent bone matrix deposition, ultimately facilitating metastatic tumor outgrowth. To address this hypothesis, I used a bone-mimetic platform and the chorioallantoic membrane (CAM) assay, a versatile model system that supports active bone matrix mineralization, to explore the effects of dox-induced MSC remodeling on tumor cell behavior. In Aim 1, I characterized the effects of dox on MSC phenotype and matrix remodeling in-vitro. Using innovative imaging and analytical approaches, in Aim 2, I developed a model system to quantitatively assess changes in bone matrix composition and structure during active mineralization. Lastly, in Aim 3, I investigated how dox-induced MSC matrix remodeling during matrix mineralization in the CAM influences tumor cell outgrowth. Our data suggest that dox-treated MSCs exhibit reduced osteogenic differentiation and mineralized matrix deposition while increasing fibrotic matrix production, enhancing breast cancer cell proliferation. This research provides critical insights into how chemotherapeutic drugs affect MSC-mediated bone matrix remodeling, inadvertently promoting tumor progression during bone metastasis in advanced breast cancer. These findings shed light on how matrix modulation affects therapeutic responses. Additionally, while this study focuses on bone metastasis, it has broader implications for understanding bone mineralization processes in other diseases, such as osteoporosis.