Systemic modeling myeloma-osteoclast interactions under normoxic/hypoxic condition using a novel computational approach

• Published in: Scientific reports 2015-08, Vol.5 (1), p.13291-13291, Article 13291
• Main Authors: Ji, Zhiwei, Wu, Dan, Zhao, Weiling, Peng, Huiming, Zhao, Shengjie, Huang, Deshuang, Zhou, Xiaobo
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/114/2391; 631/553/2695; AKT protein; Algorithms; Apoptosis; BAX protein; BIM protein; Bone marrow; Bone Marrow - metabolism; Bone Marrow - pathology; c-Jun protein; c-Myc protein; Cell activation; Cell adhesion & migration; Cell Communication; Cell growth; Cell Hypoxia; Cell Line, Tumor; Cell migration; Cell proliferation; Computer applications; Computer Simulation; Humanities and Social Sciences; Humans; Hypoxia; Linear programming; Models, Biological; multidisciplinary; Multiple myeloma; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Myc protein; Myeloma; Neoplasm Proteins - metabolism; Osteoclasts; Osteoclasts - metabolism; Osteoclasts - pathology; Oxygen - metabolism; Programming, Linear; Protein arrays; Protein kinase C; Science; Signal transduction; Transcription factors; Tumor Microenvironment
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep13291

Interaction of myeloma cells with osteoclasts (OC) can enhance tumor cell expansion through activation of complex signaling transduction networks. Both cells reside in the bone marrow, a hypoxic niche. How OC-myeloma interaction in a hypoxic environment affects myeloma cell growth and their response to drug treatment is poorly understood. In this study, we i ) cultured myeloma cells in the presence/absence of OCs under normoxia and hypoxia conditions and did protein profiling analysis using reverse phase protein array; ii ) computationally developed an Integer Linear Programming approach to infer OC-mediated myeloma cell-specific signaling pathways under normoxic and hypoxic conditions. Our modeling analysis indicated that in the presence OCs, (1) cell growth-associated signaling pathways, PI3K/AKT and MEK/ERK, were activated and apoptotic regulatory proteins, BAX and BIM, down-regulated under normoxic condition; (2) β1 Integrin/FAK signaling pathway was activated in myeloma cells under hypoxic condition. Simulation of drug treatment effects by perturbing the inferred cell-specific pathways showed that targeting myeloma cells with the combination of PI3K and integrin inhibitors potentially (1) inhibited cell proliferation by reducing the expression/activation of NF-κB, S6, c-Myc and c-Jun under normoxic condition; (2) blocked myeloma cell migration and invasion by reducing the expression of FAK and PKC under hypoxic condition.