A multicellular, microfluidic model of the human bone marrow niche in metastatic cancers

Bone metastases cause significant morbidity in solid tumors, with prostate, breast, lung, and kidney cancers representing the most common primary sources. Understanding the landscape of stromal interactions in bone and bone marrow would facilitate development of novel therapies targeting this unique metastatic niche. Mesenchymal stromal cells (MSCs) are multipotent cells in bone marrow that differentiate into osteoblasts, adipocytes, and fibroblasts and regulate immune and inflammatory responses. MSC recruitment into primary tumors enhances invasiveness of prostate adenocarcinoma, which suggests that bone marrow MSCs impact development of bone metastases in prostate cancer and promote treatment resistance. We hypothesize that multicellular interactions drive a permissive bone marrow environment for outgrowth of metastatic lesions. The goal of this study is to develop a multicellular bone stromal model from patients with solid tumors for functional and molecular analysis of cellular crosstalk. We have recently published a reconfigurable, microfluidic platform that enables culture of up to 6 different cell types in 3-dimensional matrices and multi-endpoint analysis of limited patient samples. In this study, we have modified this platform to culture patient-derived tissue, by using primary bone marrow cells from patients consented to provide bone marrow aspirate at time of radical prostatectomy. This technology allows spatiotemporal control of individual treatment conditions, enabling culture and differentiation of primary human cells in separate chips that can be reconfigured into defined microenvironments. Subsequently, specific compartments can be isolated for gene expression analysis and in-device imaging. Using this platform, we present two distinct bone marrow models. In the first model, we cultured primary human bone marrow MSCs that were induced into osteoblastic and adipocytic lineages in 3D microculture. MSCs induced invasion of prostate cancer cell lines, and paracrine crosstalk between MSCs and prostate cancer cells increased expression of IL-6, IL-8, CXCL12, and MMP-9 in MSCs. In the second model, we generated a multicellular mixed 3D culture in which osteoblasts and adipocytes spontaneously differentiate in coculture with stromal cells, osteoclasts, and leukocytes. The mixed 3D cultures generated spheroid structures that resemble stem cell components with self-renewal capability, previously called mesenspheres. Overall, we have recapitulated cellular compartments in the bone marrow niche using two complementary methods. The impact of defined molecular subtypes of cancer is now being tested to understand if specific genetic alterations promote development of invasive cancer in bone marrow. Future directions include analysis of paracrine signaling and functional interactions between disseminated cancer cells and bone marrow cellular stroma as potential therapeutic targets. Citation Format: Nan Sethakorn, David Kosoff, Erika Heninger, Jasmine Martinez Soto, Jiaquan Yu, Rahul Das, David Jarrard, Jacques Galipeau, Peiman Hematti, Scott Dehm, David J. Beebe, Joshua M. Lang. A multicellular, microfluidic model of the human bone marrow niche in metastatic cancers [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B24.