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Mathematical modelling of the role of GADD45? in the pathogenesis of multiple myeloma.

ABSTRACT: Multiple myeloma (MM) is an incurable disease with relatively high morbidity and mortality rates. Great efforts were made to develop nuclear factor-kappa B (NF-?B)-targeted therapies against MM disease. However, these treatments influence MM cells as well as normal cells, inevitably causing serious side effects. Further research showed that NF-?B signalling promotes the survival of MM cells by interacting with JNK signalling through growth arrest and DNA damage-inducible beta (GADD45?), the downstream module of NF-?B signalling. The GADD45?-targeted intervention was suggested to be an effective and MM cell-specific treatment. However, the underlying mechanism through which GADD45? promotes the survival of MM cells is usually ignored in the previous models. A mathematical model of MM is built in this paper to investigate how NF-?B signalling acts along with JNK signalling through GADD45? and MKK7 to promote the survival of MM cells. The model cannot only mimic the variations in bone cells, the bone volume and MM cells with time, but it can also examine how the NF-?B pathway acts with the JNK pathway to promote the development of MM cells. In addition, the model also investigates the efficacies of GADD45?- and NF-?B-targeted treatments, suggesting that GADD45?-targeted therapy is more effective but has no apparent side effects. The simulation results match the experimental observations. It is anticipated that this model could be employed as a useful tool to initially investigate and even explore potential therapies involving the NF-?B and JNK pathways in the future.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7277253 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Mathematical modelling of the role of GADD45β in the pathogenesis of multiple myeloma.

Zhang Yao Y Zhen Changqing C Yang Qing Q Ji Bing B

Royal Society open science 20200513 5

Multiple myeloma (MM) is an incurable disease with relatively high morbidity and mortality rates. Great efforts were made to develop nuclear factor-kappa B (NF-κB)-targeted therapies against MM disease. However, these treatments influence MM cells as well as normal cells, inevitably causing serious side effects. Further research showed that NF-κB signalling promotes the survival of MM cells by interacting with JNK signalling through growth arrest and DNA damage-inducible beta (GADD45β), the down ...[more]

PMID: 32537207

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Project description:BackgroundDespite the significant progress in the treatment of multiple myeloma (MM), the disease remains untreatable and its cure is still an unmet clinical need. Neoplastic transformation in MM is initiated in the germinal centers (GCs) of secondary lymphoid tissue (SLT) where B cells experience extensive somatic hypermutation induced by follicular dendritic cells (FDCs) and T-cell signals.ObjectiveWe reason that secreted protein acidic and rich in cysteine (SPARC), a common stromal motif expressed by FDCs at the origin (SLTs) and the destination (BM) of MM, plays a role in the pathogenesis of MM, and, here, we sought to investigate this role.MethodsThere were 107 BM biopsies from 57 MM patients (taken at different time points) together with 13 control specimens assessed for SPARC gene and protein expression and compared with tonsillar tissues. In addition, regulation of myeloma-promoting genes by SPARC-secreting FDCs was assessed in in vitro GC reactions (GCRs).ResultsSPARC gene expression was confirmed in both human primary (BM) and secondary (tonsils) lymphoid tissues, and the expression was significantly higher in the BM. Sparc was detectable in the BM and tonsillar lysates, co-localized with the FDC markers in both tissues, and stimulation of FDCs in vitro induced significantly higher levels of SPARC expression than unstimulated controls. In addition, SPARC inversely correlated with BM PC infiltration, ISS staging, and ECOG performance of the MM patients, and in vitro addition of FDCs to lymphocytes inhibited the expression of several oncogenes associated with malignant transformation of PCs.ConclusionFDC-SPARC inhibits several myelomagenic gene expression and inversely correlates with PC infiltration and MM progression. Therapeutic induction of SPARC expression through combinations of the current MM drugs, repositioning of non-MM drugs, or novel drug discovery could pave the way to better control MM in clinically severe and drug-resistant patients.

Project description:Bone marrow vascular endothelial cells (BM EC) regulate multiple myeloma pathogenesis. Identification of the mechanisms underlying this interaction could lead to the development of improved strategies for treating multiple myeloma. Here, we performed a transcriptomic analysis of human ECs with high capacity to promote multiple myeloma growth, revealing overexpression of the receptor tyrosine kinases, EPHB1 and EPHB4, in multiple myeloma-supportive ECs. Expression of ephrin B2 (EFNB2), the binding partner for EPHB1 and EPHB4, was significantly increased in multiple myeloma cells. Silencing EPHB1 or EPHB4 in ECs suppressed multiple myeloma growth in coculture. Similarly, loss of EFNB2 in multiple myeloma cells blocked multiple myeloma proliferation and survival in vitro, abrogated multiple myeloma engraftment in immune-deficient mice, and increased multiple myeloma sensitivity to chemotherapy. Administration of an EFNB2-targeted single-chain variable fragment also suppressed multiple myeloma growth in vivo. In contrast, overexpression of EFNB2 in multiple myeloma cells increased STAT5 activation, increased multiple myeloma cell survival and proliferation, and decreased multiple myeloma sensitivity to chemotherapy. Conversely, expression of mutant EFNB2 lacking reverse signaling capacity in multiple myeloma cells increased multiple myeloma cell death and sensitivity to chemotherapy and abolished multiple myeloma growth in vivo. Complementary analysis of multiple myeloma patient data revealed that increased EFNB2 expression is associated with adverse-risk disease and decreased survival. This study suggests that EFNB2 reverse signaling controls multiple myeloma pathogenesis and can be therapeutically targeted to improve multiple myeloma outcomes.SignificanceEphrin B2 reverse signaling mediated by endothelial cells directly regulates multiple myeloma progression and treatment resistance, which can be overcome through targeted inhibition of ephrin B2 to abolish myeloma.

Project description:It is increasingly apparent that cancer cells, in addition to remodelling their metabolism to survive and proliferate, adapt and manipulate the metabolism of other cells. This property may be a telling sign that pre-clinical tumour metabolism studies exclusively utilising in-vitro mono-culture models could prove to be limited for uncovering novel metabolic targets able to translate into clinical therapies. Although this is increasingly recognised, and work towards addressing the issue is becoming routinary much remains poorly understood. For instance, knowledge regarding the biochemical mechanisms through which cancer cells manipulate non-cancerous cell metabolism, and the subsequent impact on their survival and proliferation remains limited. Additionally, the variations in these processes across different cancer types and progression stages, and their implications for therapy, also remain largely unexplored. This study employs an interdisciplinary approach that leverages the predictive power of mathematical modelling to enrich experimental findings. We develop a functional multicellular in-silico model that facilitates the qualitative and quantitative analysis of the metabolic network spawned by an in-vitro co-culture model of bone marrow mesenchymal stem- and myeloma cell lines. To procure this model, we devised a bespoke human genome constraint-based reconstruction workflow that combines aspects from the legacy mCADRE & Metabotools algorithms, the novel redHuman algorithm, along with 13C-metabolic flux analysis. Our workflow transforms the latest human metabolic network matrix (Recon3D) into two cell-specific models coupled with a metabolic network spanning a shared growth medium. When cross-validating our in-silico model against the in-vitro model, we found that the in-silico model successfully reproduces vital metabolic behaviours of its in-vitro counterpart; results include cell growth predictions, respiration rates, as well as support for observations which suggest cross-shuttling of redox-active metabolites between cells.

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Mathematical modelling of the role of GADD45? in the pathogenesis of multiple myeloma.

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Mathematical modelling of the role of GADD45β in the pathogenesis of multiple myeloma.

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