JAM-A as a Prognostic Factor and New Therapeutic Target in Multiple Myeloma

Abstract

Cell adhesion in the multiple myeloma (MM) microenvironment is a mechanism by which MM plasma cells escape the effects of therapy and survive. To improve clinical strategies and overcome drug resistance, approaches directed to both MMPCs and bone marrow microenvironment are under investigation. Here, we examined the cell membrane protein Junctional adhesion molecule-A (JAM-A) as a clinical biomarker and novel therapeutic target for MM. We evaluated JAM-A expression by real time PCR (RT-PCR), flow cytometry and immunofluorescence microscopy in 132 MM patients at different stages and various MM cell lines. Next, we measured the concentrations of soluble JAM-A from MM and healthy subjects sera by enzyme linked immune assay (ELISA). We investigated JAM-A functionally in vitro and in vivo by transient gene silencing (siRNA) and with blocking antibodies. Patient-derived plasma cells (MMPCs) expressed increased JAM-A expression levels when compared to control PC from healthy individuals. Elevated JAM-A expression correlated with poor prognosis (Figure 1A,B). Furthermore, soluble JAM-A was significantly increased in MM patient sera when compared to healthy subjects. Additionally, MM cell lines showed high expression of both membrane and cytoplasmic JAM-A. Consequently, inhibition of JAM-A using specific siRNA treatment resulted in diminished tumorigenic potential, including decreased colony formation, chemotaxis and migration. Importantly, treatment of luciferase+RPMI-8226 MM bearing NSG with a JAM-A blocking monoclonal antibody reduced significantly MM progression and dissemination in vivo when compared to MM bearing mice that received an non-specific isotype control antibody (Figure 1C). Conclusively, our data suggest that JAM-A can serve as a biomarker of malignancy in MM patients. Soluble plasma JAM-A could contribute to serum-based clinical stratification. Furthermore, therapeutic targeting of JAM-A appears attractive for clinical translation. Figure 1 Figure 1. Disclosures Einsele: Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria.

Identification of Key Genes and Pathways in Myeloma side population cells by Bioinformatics Analysis

“…It has been uncovered that some integrins were detected in high levels in MM, while in non-detectable levels in nonactive MM and MGUS patients, suggesting the adhesion molecules support the interactions between MM and the microvasculature and facilitate disease progression [70]. Furthermore, junctional adhesion molecule A has been identified as a key mediator of MM progression by promoting MM-associated angiogenesis and an independent prognostic factor for both newly diagnosed MM and relapsed/ refractory MM [71,72]. Similarly, our enrichment analysis of up-regulated DEGs had identified positive regulation of angiogenesis and cell adhesion, demonstrating that myeloma SP cells may be relevant to angiogenesis and cell adhesion to propagate MM progression.…”

Bone metastasis as primary presentation of pancreatic ductal adenocarcinoma: A case report and literature review

“…12 As in other several solid and hematologic cancer, [13][14][15] the tumor microenvironment emerged as a pivotal driver of metastatic niche 16 being correlated at the same time to cell-adhesion dependent and independent drug-resistance development. [17][18][19][20] Thus, several approaches have been envisioned in order to molecularly overcome this malignant phenotype, in order to target both the cancer cells and the tumoral milieu. [21][22][23] Variable incidence of bone metastases from PDAC reported in literature (from 5% to 20%) should be conditioned by either the possible overlapping between symptoms related to the primary tumor and bone localization or the longer survival obtained in the last few years due the availability of new and more active chemotherapy regimens in both adjuvant and advanced settings.…”

“…The metastatic process is strictly connected to tumor intrinsic and extrinsic characteristics . As in other several solid and hematologic cancer, the tumor microenvironment emerged as a pivotal driver of metastatic niche being correlated at the same time to cell‐adhesion dependent and independent drug‐resistance development . Thus, several approaches have been envisioned in order to molecularly overcome this malignant phenotype, in order to target both the cancer cells and the tumoral milieu .…”

Oncogenic Signaling Pathways in Cancer: An Overview

“…This type of development is regulated by various highly organized processes, including TNF, Notch, Wnt, TGFβ and a number of growth factors [101-103]. EMT is characterized by the decrease of E-cadherin cell-cell adhesion molecules, which drives tumor progression [104,105], loss of apical-basal polarity, anchorage independence in some contexts, the adoption of a more fibroblast-like appearance and the acquisition of stem or progenitor-cell phenotypes as well. These would augment the capacity of the cell to invade other tissues and trigger tumors at distant sites.…”