Junctional adhesion molecule C expression specifies a CD138low/neg multiple myeloma cell population in mice and humans

Abstract

Deregulation such as overexpression of adhesion molecules influences cancer progression and survival. Metastasis of malignant cells from their primary tumor site to distant organs is the most common reason for cancer-related deaths. Junctional adhesion molecule (JAM)-C, a member of the Ig-like JAM family, can homodimerize and aid cancer cell migration and metastasis. Here we show that this molecule is dynamically expressed on multiple myeloma (MM) cells in the marrow and co-localizes with blood vessels within the bone marrow of mice and humans. Additionally, JAM-C upregulation inversely correlates with the downregulation of the canonical plasma cell marker CD138 (syndecan-1), whose surface expression has recently been found to dynamically regulate a switch between MM growth in situ and MM dissemination. Moreover, targeting JAM-C in a syngeneic in vivo MM model ameliorates MM progression and improves outcome. Overall, our data demonstrate that JAM-C might serve not only as an additional novel diagnostic biomarker but also as a therapeutic target in MM disease.

Drug resistance in multiple myeloma: Soldiers and weapons in the bone marrow niche

“…MM CSCs differ from normal stem cells in terms of their genetic and epigenetic features, with their phenotype determined by the nature of the mutations ( 145 ). In MM, the phenotype of CSCs is not precisely known ( 146 ), with some studies claiming that they resemble CD138− B cells ( 9 , 147 ). Human MM cell lines were shown to contain small subpopulations of CD138− cells with greater clonogenic potential than the corresponding CD138+ cells.…”

“…Brandl et al. found a higher proportion of CD138+ cells in proliferating and engrafted cells, and a lower proportion or the absence of CD138 low/CD138− cells, shown to be highly positive for the cell-adhesion molecule JAM-C (junctional adhesion molecule-C, 147 ). More motile and thus faster disseminating.…”

The Route of the Malignant Plasma Cell in Its Survival Niche: Exploring “Multiple Myelomas”

“…MM grows and evolves through persistent crosstalk with the surrounding niche, while distinct gatekeepers and immune-tolerogenic environments often emerge simultaneously in response to this crosstalk. Accordingly, combining anti-tumor therapy and immunotherapy could be a promising and effective strategy to slope the equilibrium of the MM ecosystem, and improve patient outcomes, as already obtained in other malignancies [133][134][135][136][137][138]: this approach will enable the development of personalized therapy for "multiple myelomas" [139,140].…”

Understanding the Bioactivity and Prognostic Implication of Commonly Used Surface Antigens in Multiple Myeloma

“…Recently, CD138 high MM cells were characterized by a proliferative but static phenotype, as opposed to CD138 low MM cells which were more motile and disseminative [ 29 ]. Junctional Adhesion Molecule-C was described as a key regulator in the switch between these two states [ 32 ]. These recent findings may explain earlier reports of CD138 shedding into the plasma [ 33 ], and correlating high plasma levels of soluble CD138 with a dismal prognosis [ 34 ].…”