Proteomic profiling in plasma cell disorders: a feasibility study

Mailankody, Sham; Devlin, Sean M.; Korde, Neha; Lendvai, Nikoletta; Lesokhin, Alexander M.; Landau, Heather; Hassoun, Hani; Ballagi, Andrea; Ekman, Daniel; Chung, David J.; Patel, Minal; Koehne, Guenther; Giralt, Sergio; Landgren, Ola

doi:10.1080/10428194.2016.1258699

Cited by 7 publications

(4 citation statements)

References 7 publications

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“…Although we have described this mechanism in tumor cell lines (melanoma and myeloma), it is well-known that HPSE (Kelly et al, 2003;Vornicova et al, 2016), VEGFR2 (Giatromanolaki et al, 2010;Mailankody et al, 2017;Molhoek et al, 2011), CXCR4 (Kim et al, 2006;Scala et al, 2005), VLA-4 (Mullen et al, 2008;Soodgupta et al, 2016) and Sdc1 (Maisnar et al, 2006;Orecchia et al, 2013) are expressed in individuals with melanoma and myeloma, supporting the clinical relevance of our findings. 6.…”

Section: Discussionsupporting

confidence: 85%

VLA-4 phosphorylation during tumor and immune cell migration relies on its coupling to VEGFR2 and CXCR4 by syndecan-1

Jung

Beauvais

Adams

et al. 2019

Journal of Cell Science

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When targeted by the tumor-promoting enzyme heparanase, cleaved and shed syndecan-1 (Sdc1) then couples VEGFR2 (also known as KDR) to VLA-4, activating VEGFR2 and the directed migration of myeloma cells. But how VEGFR2 activates VLA-4-mediated motility has remained unknown. We now report that VEGFR2 causes PKAmediated phosphorylation of VLA-4 on S988, an event known to stimulate tumor metastasis while suppressing cytotoxic immune cells. A key partner in this mechanism is the chemokine receptor CXCR4, a well-known mediator of cell motility in response to gradients of the chemokine SDF-1 (also known as CXCL12). The entire machinery necessary to phosphorylate VLA-4, consisting of CXCR4, AC7 (also known as ADCY7) and PKA, is constitutively associated with VEGFR2 and is localized to the integrin by Sdc1. VEGFR2 carries out the novel phosphorylation of Y135 within the DRY microswitch of CXCR4, sequentially activating Gα i βγ, AC7 and PKA, which phosphorylates S988 on the integrin. This mechanism is blocked by a syndecanmimetic peptide (SSTN VEGFR2), which, by preventing VEGFR2 linkage to VLA-4, arrests tumor cell migration that depends on VLA-4 phosphorylation and stimulates the LFA-1-mediated migration of cytotoxic leukocytes.

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Section: Discussionsupporting

confidence: 85%

VLA-4 phosphorylation during tumor and immune cell migration relies on its coupling to VEGFR2 and CXCR4 by syndecan-1

Jung

Beauvais

Adams

et al. 2019

Journal of Cell Science

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“…Proteomic evaluation of all MGUS, SMM, and MM patients revealed a linear trend in vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor 2 (VEGFR2), and interleukin-6 (IL-6) levels across MM stages. VEGFR2 downregulation was observed with the courses of MGUS, SMM, and MM [92]. Furthermore, the VEGFR2-604TT genotype is more common and associated with MM patients with a higher disease burden.…”

Section: Proteomics Alteration In MM 41 Monoclonal Gammopathy Of Unde...mentioning

confidence: 90%

Proteomic Alteration in the Progression of Multiple Myeloma: A Comprehensive Review

et al. 2023

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Multiple myeloma (MM) is an incurable hematologic malignancy. Most MM patients are diagnosed at a late stage because the early symptoms of the disease can be uncertain and nonspecific, often resembling other, more common conditions. Additionally, MM patients are commonly associated with rapid relapse and an inevitable refractory phase. MM is characterized by the abnormal proliferation of monoclonal plasma cells in the bone marrow. During the progression of MM, massive genomic alterations occur that target multiple signaling pathways and are accompanied by a multistep process involving differentiation, proliferation, and invasion. Moreover, the transformation of healthy plasma cell biology into genetically heterogeneous MM clones is driven by a variety of post-translational protein modifications (PTMs), which has complicated the discovery of effective treatments. PTMs have been identified as the most promising candidates for biomarker detection, and further research has been recommended to develop promising surrogate markers. Proteomics research has begun in MM, and a comprehensive literature review is available. However, proteomics applications in MM have yet to make significant progress. Exploration of proteomic alterations in MM is worthwhile to improve understanding of the pathophysiology of MM and to search for new treatment targets. Proteomics studies using mass spectrometry (MS) in conjunction with robust bioinformatics tools are an excellent way to learn more about protein changes and modifications during disease progression MM. This article addresses in depth the proteomic changes associated with MM disease transformation.

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“…The same holds true for proteomic screening of plasma samples targeting proteins showing aberrant expression. These may provide an additional means of identifying heterogeneity, with potential for implementation as a biomarker approach in routine hospital laboratories [ 60 ]. However, a comprehensive longitudinal study combining multi-region sequencing including FLs and circulating cells/DNA, as well as protein profiling, has not been performed yet.…”

Section: Overcoming Tumor Heterogeneitymentioning

confidence: 99%

The Impact of Tumor Heterogeneity on Diagnostics and Novel Therapeutic Strategies in Multiple Myeloma

Rasche

Kortüm

Raab

et al. 2019

IJMS

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Myeloma is characterized by extensive inter-patient genomic heterogeneity due to multiple different initiating events. A recent multi-region sequencing study demonstrated spatial differences, with progression events, such as TP53 mutations, frequently being restricted to focal lesions. In this review article, we describe the clinical impact of these two types of tumor heterogeneity. Target mutations are often dominant at one site but absent at other sites, which poses a significant challenge to personalized therapy in myeloma. The same holds true for high-risk subclones, which can be locally restricted, and as such not detectable at the iliac crest, which is the usual sampling site. Imaging can improve current risk classifiers and monitoring of residual disease, but does not allow for deciphering the molecular characteristics of tumor clones. In the era of novel immunotherapies, the clinical impact of heterogeneity certainly needs to be re-defined. Yet, preliminary observations indicate an ongoing impact of spatial heterogeneity on the efficacy of monoclonal antibodies. In conclusion, we recommend combining molecular tests with imaging to improve risk prediction and monitoring of residual disease. Overcoming intra-tumor heterogeneity is the prerequisite for curing myeloma. Novel immunotherapies are promising but research addressing their impact on the spatial clonal architecture is highly warranted.

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Proteomic profiling in plasma cell disorders: a feasibility study

Cited by 7 publications

References 7 publications

VLA-4 phosphorylation during tumor and immune cell migration relies on its coupling to VEGFR2 and CXCR4 by syndecan-1

VLA-4 phosphorylation during tumor and immune cell migration relies on its coupling to VEGFR2 and CXCR4 by syndecan-1

Proteomic Alteration in the Progression of Multiple Myeloma: A Comprehensive Review

The Impact of Tumor Heterogeneity on Diagnostics and Novel Therapeutic Strategies in Multiple Myeloma

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