Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity.
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.
[1] Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Douglas W
DW
McMillin
Jake
J
Delmore
Ellen
E
Weisberg
Joseph M
JM
Negri
D Corey
DC
Geer
Steffen
S
Klippel
Nicholas
N
Mitsiades
Robert L
RL
Schlossman
Nikhil C
NC
Munshi
Andrew L
AL
Kung
James D
JD
Griffin
Paul G
PG
Richardson
Kenneth C
KC
Anderson
Constantine S
CS
Mitsiades
D000970:Antineoplastic Agents / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D008163:Luminescent Measurements / Q000379:methods*; D009025:Morpholines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000970:Antineoplastic Agents; D009025:Morpholines; D011687:Purines; C484369:2-(4-morpholinoanilino)-6-cyclohexylaminopurine