title: Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model.
abstract: Clonal proliferation of plasma cells within the bone marrow (BM) affects local cells, such as mesenchymal stromal cells (MSCs), leading to osteolysis and fatality in multiple myeloma (MM). Consequently, there is an urgent need to find better mechanisms of inhibiting myeloma growth and osteolytic lesion development. To meet this need and accelerate clinical translation, better models of myeloma within the BM are required. Herein we have developed a clinically relevant, three-dimensional (3D) myeloma BM coculture model that mimics bone cell/cancer cell interactions within the bone microenvironment. The coculture model and clinical samples were used to investigate myeloma growth, osteogenesis inhibition, and myeloma-induced abnormalities in MM-MSCs. This platform demonstrated myeloma support of capillary-like assembly of endothelial cells and cell adhesion-mediated drug resistance (CAM-DR). Also, distinct normal donor (ND)- and MM-MSC miRNA (miR) signatures were identified and used to uncover osteogenic miRs of interest for osteoblast differentiation. More broadly, our 3D platform provides a simple, clinically relevant tool to model cancer growth within the bone-useful for investigating skeletal cancer biology, screening compounds, and exploring osteogenesis. Our identification and efficacy validation of novel bone anabolic miRs in MM opens more opportunities for novel approaches to cancer therapy via stromal miR modulation.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Michaela R
authors.identifier: http://orcid.org/0000-0003-2884-6481
authors.initials: MR
authors.lastname: Reagan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishima
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Siobhan V
authors.identifier: http://orcid.org/0000-0001-6357-6064
authors.initials: SV
authors.lastname: Glavey
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Salomon
authors.initials: S
authors.lastname: Manier
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Zhi Ning
authors.initials: ZN
authors.lastname: Lu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Memarzadeh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Yosra
authors.initials: Y
authors.lastname: Aljawai
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA;
authors.forename: Jiantao
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Brigham and Women's Hospital, Boston, MA; and.
authors.forename: John E
authors.initials: JE
authors.lastname: Ready
authors.affiliation: Department of Biomedical Engineering, Tufts University, Medford MA.
authors.forename: David L
authors.initials: DL
authors.lastname: Kaplan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D001854:Bone Marrow Cells / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology; D008954:Models, Biological; D009101:Multiple Myeloma / Q000473:pathology*; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology*; D061251:Primary Cell Culture / Q000379:methods*; D055153:Stem Cell Niche / Q000502:physiology; D054457:Tissue Scaffolds