Background: Multiple Myeloma (MM) is a cancer of plasma cells that accumulate in the bone marrow (BM). Despite recent advances in treatments, it remains incurable and there is urgent need of novel and more effective therapies. However, there has recently surfaced a new treatment paradigm that shows great promise to improve patient outcome by disrupting the tropism that the BM microenvironment, the `soil', plays on MM cells, the `seeds'. Since BM angiogenesis is a hallmark of MM progression that correlates with disease stage, it became evident that among the interactions between MM cells and the BM microenvironment, those with BM endothelial cells (BMECs) must play an important role in MM progression. Preliminary data: During studies of the interaction of MM cells with the BM microenvironment, we uncovered a critical role of canonical Wnt signaling, a conduit for cell-cell communication and tropism culminating in transcriptional activation of pro- migration, proliferation, and survival genes. The terminal effector of Wnt signaling is a transcriptional complex that includes two other signaling proteins, -catenin and BCL9. Moreover, during immunohistochemical studies using BM tissue microarrays, we observed restricted and high-level BCL9 expression in BMECs but not other BM cells. In addition, using proteomic analysis we have documented that extracellular Cyclophilin A (eCyPA) is a downstream transcriptional target of the Wnt/-catenin/BCL9 complex, which is secreted by BMECs but not other BM stromal cells and promote pleiotropic signaling changes in MM including enhanced expression of CD14, the know receptor of eCyPA. Furthermore, knockdown of either eCyPA in BMECs or CD147 in MM cells markedly decreased migration and proliferation of MM cells. Working hypothesis: (i) signaling from BMECs is essential for MM progression; (ii) eCyPA plays critical roles in the signaling output from BMECs that modulate migration, invasion, colonization, growth, survival, and drug resistance of MM cells. Thus, targeting the interaction between eCyPA and its cognate receptor CD147 on MM cells is therapeutic for MM, particularly for cases with acquired resistance to standard chemotherapy. Goals: (i) to further characterize the role of BMECs in MM progression, (ii) to validate the role of the eCyPA/CD147 signaling complex as therapeutic target for MM, (iii) to identify and functionally characterize additional signaling molecules secreted by BMECs that promote MM progression, and (iii) to develop a high throughput screening assay to identify small molecule inhibitors of eCyPA/CD147 interaction for future development of targeted therapies for MM. Expected results: i) validate role of eCyPA/CD147 signaling complex as effective nontoxic target for MM therapy; ii) identification of novel potential biomarkers of MM progression and therapeutic targets. Broader implications for medicine: Development of more effective targeted therapies for MM and other hematologic malignancies that express CD147 and 'home in' the BM.

Public Health Relevance

Multiple myeloma (MM) is the second most frequent hematologic cancer after non-Hodgkin's lymphoma, and remains incurable despite tremendous efforts to develop curative therapy. MM is characterized by accumulation of malignant plasma cells in the bone marrow (BM) niche, and cells within the BM play critical roles in the establishment and progression of this deadly neoplasm. Here we propose to target the eCyPA/CD147 signaling complex as a way to disrupt the functional interaction between MM cells and BM endothelial cells, which secrete eCYPA that promote disease progression through binding to CD147 the signaling partner expressed by MM cells. The proposed studies are significant to public health in that their ultimate goal is to improve patient outcome through therapies that alleviate suffering, replace less efficacious options, and reduce the overall cost o treatment cost of not only MM, but potentially also other hematologic malignancies that 'home in' the BM.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Microenvironment Study Section (TME)
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Howcroft, Thomas K
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Dana-Farber Cancer Institute
United States
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Sewastianik, Tomasz; Jiang, Meng; Sukhdeo, Kumar et al. (2017) Constitutive Ras signaling and Ink4a/Arf inactivation cooperate during the development of B-ALL in mice. Blood Adv 1:2361-2374
Zhu, Di; Wang, Zhongqiu; Zhao, Jian-Jun et al. (2015) The Cyclophilin A-CD147 complex promotes the proliferation and homing of multiple myeloma cells. Nat Med 21:572-80