Conventional anticancer drug screening is typically performed in the absence of accessory cells of the tumor microenvironment, which can profoundly alter
antitumor drug activity. To address this limitation, we developed the
tumor cell-specific in vitro bioluminescence imaging (CS-BLI) assay.
Tumor cells (for example, myeloma,
leukemia and solid
tumors) stably expressing
luciferase are cultured with nonmalignant accessory cells (for example, stromal cells) for selective quantification of
tumor cell viability, in presence versus absence of stromal cells or drug treatment. CS-BLI is high-throughput scalable and identifies stroma-induced chemoresistance in diverse
malignancies, including
imatinib resistance in leukemic cells. A stroma-induced signature in
tumor cells correlates with adverse clinical prognosis and includes signatures for activated Akt, Ras,
NF-kappaB, HIF-1alpha, myc, hTERT and IRF4; for biological aggressiveness; and for self-renewal. Unlike conventional screening, CS-BLI can also identify agents with increased activity against
tumor cells interacting with stroma. One such compound,
reversine, shows more potent activity in an orthotopic model of diffuse myeloma bone lesions than in conventional subcutaneous xenografts. Use of CS-BLI, therefore, enables refined screening of candidate
anticancer agents to enrich preclinical pipelines with potential
therapeutics that overcome stroma-mediated drug resistance and can act in a synthetic lethal manner in the context of
tumor-stroma interactions.