An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells.
In this work we describe a novel approach that combines ex vivo drug sensitivity assays and digital image analysis to estimate chemosensitivity and heterogeneity of patient-derived multiple myeloma (MM) cells. This approach consists in seeding primary MM cells freshly extracted from bone marrow aspirates into microfluidic chambers implemented in multi-well plates, each consisting of a reconstruction of the bone marrow microenvironment, including extracellular matrix (collagen or basement membrane matrix) and stroma (patient-derived mesenchymal stem cells) or human-derived endothelial cells (HUVECs). The chambers are drugged with different agents and concentrations, and are imaged sequentially for 96 hr through bright field microscopy, in a motorized microscope equipped with a digital camera. Digital image analysis software detects live and dead cells from presence or absence of membrane motion, and generates curves of change in viability as a function of drug concentration and exposure time. We use a computational model to determine the parameters of chemosensitivity of the tumor population to each drug, as well as the number of sub-populations present as a measure of tumor heterogeneity. These patient-tailored models can then be used to simulate therapeutic regimens and estimate clinical response.
Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute; Ariosto.Silva@moffitt.org.
Ariosto
A
Silva
Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute.
Timothy
T
Jacobson
Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute.
Mark
M
Meads
Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute.
Allison
A
Distler
Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute.
Kenneth
K
Shain
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D042783:Endothelial Cells / Q000166:cytology; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D056656:Lab-On-A-Chip Devices; D059630:Mesenchymal Stem Cells / Q000166:cytology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents