Abstract IA019: Collagen mineralization and its role in breast cancer bone metastasis

Abstract

Abstract Skeletal metastasis of breast cancer is associated with changes in bone mineral density, therapy resistance, and poor clinical prognosis. Most emphasis to date has been placed on studying the role of bone and marrow cells in this process, but the functional contribution of skeletal extracellular matrix (ECM) remains largely unclear. Better understanding these connections is critical as mineralized collagen, the basic building block of bone, is a key component of the osteogenic niche that tumor cells target during dissemination and that changes as a function of diet, age, and exercise. Using correlative materials science and tissue engineering approaches, we have characterized metastasis-relevant bone matrix characteristics across multiple length scales and recapitulated these properties in vitro to investigate the functional relationship between collagen mineralization and tumor cell phenotype. Breast cancer cells cultured on mineralized substrates exhibited reduced adhesion forces and accordingly reduced collagen fiber alignment relative to cells cultured on control collagen. These changes were attributed to mineral-mediated differences in collagen stress relaxation and altered mechanosignaling with consequences on tumor cell migration and expression of cancer stem cell markers. RNAseq analysis in combination with functional studies confirmed that tumor cells interacting with control vs. mineralized collagen exhibited altered proliferative and therapy-resistant capability. In vivo studies confirmed the relevance of bone matrix mineralization to secondary tumor growth and therapy resistance. These results suggest that changes in collagen mineralization directly impact hallmark features of skeletal metastasis including tumor cell dissemination, growth, and therapy resistance and underline the critical importance of bone mineral in the pathogenesis of breast cancer bone metastasis. Citation Format: Claudia Fischbach. Collagen mineralization and its role in breast cancer bone metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA019.