Abstract 696: Spatially patterned, 3D in vitro models of cancer metastasis to bone for elucidating key drivers of metastasis and drug discovery

Abstract

Abstract Bone is one of the most common sites of cancer metastasis, affecting more than 70% of patients with advanced breast cancer and prostate cancer. Despite its prevalence, there are still no effective treatments for bone metastasis, leading to very poor survival rates and the mechanism by which certain cancer cells preferentially spread to the bones remains poorly understood. Thus, there is a critical need to develop in vitro experimental models that can mimic key aspects of bone metastasis development to elucidate driving mechanisms of this disease and expedite the discovery of novel drug candidates. To address this unmet need, here we report a spatially patterned, 3D in vitro model which mimics cancer metastasis to bone by incorporating interactions with multiple tissue types. The model is composed of an outer ring of tissue engineered bone derived from 3D osteogenic differentiation of human mesenchymal stem cells (hMSCs), and a center containing cancer cells. This interface between these two tissues mimics the way cancer cells invade into the bones through the bone marrow/bone interface and allows us to track the invasion of fluorescently labeled cancer cells into bone using confocal imaging. Cancer cells and hMSCs were also labeled with orthogonal luciferases (FireflyLuc and NanoLuc), allowing for simultaneous quantification of cancer cell proliferation and osteoblast survival using BLI. We tested the ability of this model to recapitulate known characteristics of in vivo bone metastases including tissue-specific invasion, cancer aggressiveness, cancer-induced bone resorption, and in vivo drug response. Using multiple established breast cancer (MDA-MB-231 and MCF-7) and prostate cancer (LNCaP and PC-3) cell lines, we demonstrate that such spatially patterned coculture models mimic the preferential invasion of cancer cells to bone, but not cartilage or muscle (negative controls) and the rate of invasion in this 3D model correlated with the level of cancer cell aggressiveness. To mimic the effect of cancer invasion on bone remodeling, we established a triculture model in which osteoclasts were seeded over the tissue engineered bone. Micro-computed tomography imaging validated that this model could recapitulate cancer-induced bone resorption, and the degree of bone resorption also correlated with cancer cell aggressiveness. Using parathyroid hormone as a model drug, we demonstrate this 3D model recapitulates drug responses consistent with what has been observed using in vivo mouse models. Such spatially patterned 3D models can provide a scalable platform for drug screening with substantially reduced time and cost compared to animal models. Furthermore, integrating these 3D cancer metastasis models with high-dimensional methods, such as single-cell RNAseq could expedite the discovery of novel druggable drivers of bone metastasis. Citation Format: Eva C. González Díaz, Michelle Tai, Callan E. Monette, Joy Wu, Fan Yang. Spatially patterned, 3D in vitro models of cancer metastasis to bone for elucidating key drivers of metastasis and drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 696.