Targeting the biophysical properties of the myeloma initiating cell niches: a pharmaceutical synergism analysis using multi-scale agent-based modeling.
Multiple myeloma, the second most common hematological cancer, is currently incurable due to refractory disease relapse and development of multiple drug resistance. We and others recently established the biophysical model that myeloma initiating (stem) cells (MICs) trigger the stiffening of their niches via SDF-1/CXCR4 paracrine; The stiffened niches then promote the colonogenesis of MICs and protect them from drug treatment. In this work we examined in silico the pharmaceutical potential of targeting MIC niche stiffness to facilitate cytotoxic chemotherapies. We first established a multi-scale agent-based model using the Markov Chain Monte Carlo approach to recapitulate the niche stiffness centric, pro-oncogenetic positive feedback loop between MICs and myeloma-associated bone marrow stromal cells (MBMSCs), and investigated the effects of such intercellular chemo-physical communications on myeloma development. Then we used AMD3100 (to interrupt the interactions between MICs and their stroma) and Bortezomib (a recently developed novel therapeutic agent) as representative drugs to examine if the biophysical properties of myeloma niches are drugable. Results showed that our model recaptured the key experimental observation that the MBMSCs were more sensitive to SDF-1 secreted by MICs, and provided stiffer niches for these initiating cells and promoted their proliferation and drug resistance. Drug synergism analysis suggested that AMD3100 treatment undermined the capability of MICs to modulate the bone marrow microenvironment, and thus re-sensitized myeloma to Bortezomib treatments. This work is also the first attempt to virtually visualize in 3D the dynamics of the bone marrow stiffness during myeloma development. In summary, we established a multi-scale model to facilitate the translation of the niche-stiffness centric myeloma model as well as experimental observations to possible clinical applications. We concluded that targeting the biophysical properties of stem cell niches is of high clinical potential since it may re-sensitize tumor initiating cells to chemotherapies and reduce risks of cancer relapse.
Department of Radiology, The Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
Jing
J
Su
College of Computer and Information Science, Southwest University, Chongqing, People's Republic of China ; School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, United States of America.
Le
L
Zhang
Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, Texas, United States of America.
Wen
W
Zhang
Department of Pathology, The Methodist Hospital Research Institute, Weil Cornell Medical College, Houston, Texas, United States of America.
Dong Song
DS
Choi
Department of Pathology, The Methodist Hospital Research Institute, Weil Cornell Medical College, Houston, Texas, United States of America.
Jianguo
J
Wen
Department of Mathematical Sciences, Michigan Technological University, Houghton, Michigan, United States of America.
Beini
B
Jiang
Department of Pathology, Florida Hospital, University of Central Florida, Orlando, Florida, United States of America.
Chung-Che
CC
Chang
Department of Radiology, The Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
Xiaobo
X
Zhou
D001596:Benzylamines; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D054377:Chemokine CXCL12 / Q000378:metabolism; D003198:Computer Simulation; D000080027:Cyclams; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008390:Markov Chains; D008954:Models, Biological; D009010:Monte Carlo Method; D009101:Multiple Myeloma / Q000188:drug therapy*; D014411:Neoplastic Stem Cells / Q000502:physiology*; D019899:Paracrine Communication / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000502:physiology*
D001596:Benzylamines; D001897:Boronic Acids; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D011719:Pyrazines; D000069286:Bortezomib; C088327:plerixafor