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Blocking JAM-A on BM endothelial cells in MM
adhere to tumor necrosis factor-a-primed endothelial cells in the presence of an anti-ENO-1 monoclonal antibody. Consequently, decreased migration of the myeloid-derived suppressor cells reduced in situ immunosuppression, enhancing T-cell-mediated immunity against malignant cells.38,39
We found that JAM-A overexpression in MMEC strongly correlated with the expression of ADAMTS1, a regulator of angiogenesis40 and immune-surveillance,41 which appears to play a central role in preparing a favorable BM milieu.42 We also identified that the expression of JAM-A on the surface of MMEC was inversely correlated with ADAM17 expres- sion. Conversely, sJAM-A release correlated directly with ADAM17 upregulation, a mechanism described for endothelial cells in inflammation.9 ADAM17 upregulation has also been observed in MM in the context of fractalkine release,43 which identifies this system as a potential novel therapeutic target in MM patients to disrupt a vicious circle enhancing the MM niche.
as a new player in MM-associated angiogenesis able to refine the prognostic stratification of patients, especially those with more advanced disease.
The close link between MM and the BM microenviron- ment appears paradigmatic for MM evolution and disease progression. We connected the interaction of MMEC with MM-cells via the adhesion molecule JAM-A. Our data point towards a vicious cycle of JAM-A overexpression on MMEC reflected by a higher JAM-A expression on the tumoral counterpart. Shed from the cell surface, sJAM-A enhances the establishment of homophilic JAM-A com- plexes fostering MM niche formation. Finally, our results may lead to the development of JAM-A-based therapeutic strategies directed against MM-interactions with the tumor microenvironment (Figure 7A-D). Clearly, these findings need to be confirmed in a larger population of patients in a carefully designed, prospective, clinical study.
Disclosures
No conflicts of interest to disclosure.
Contributions
AGS, MCDV, VR, HE, AV and ABe designed and performed research, analyzed and interpreted data and wrote the manu- script; AGS, MCDV, PL, GC, PTG, GDL, ABr, EH, HR-W, DR performed research and analyzed data; AGS, MCDV, AA, PB, GC, FPB, AM, SDS, TS, ABa, MAF, WK, AR and ST ana- lyzed data; AGS, HE, RR, LR, PD, KMK, VR and AV provided patients’ samples; AGS, MCDV, CT, MC, VR, AV, HE and ABe designed research, interpreted data, and edited the manu- script; all authors revised the manuscript and approved its submis- sion. VR and HE contributed equally to this study. AV and ABe contributed equally to the conception and design of this study.
Acknowledgments
The authors acknowledge the Multiple Myeloma Research Foundation for providing an updated and comprehensive real-life MM dataset for the international scientific community. The in sil- ico analysis and the relative clinical correlation were generated as part of the Multiple Myeloma Research Foundation Personalized Medicine Initiative. We thank the members of the laboratories of Beilhack and Vacca for lively discussions. We also thank Drs. Julia Delgado Tascón, Claudia Siverino and Marco Metzger, and Mss Katharina Schmiedgen, Charlotte Botz-Von Drathen, Hannah Manz and Vittoria Musci for technical support and valuable discussions. Public consulted datasets are available at https://research.mmrf.org, CoMMpass longitudinal, prospective observational study (release IA12).
Funding
This work was supported by the Bayerische Forschungsstiftung consortium FortiTher (WP2TP3), the Deutsche Forschungsgemeinschaft mBone consortium (2084/1, 401253051), by the Italian Association for Cancer Research (AIRC) through an Investigator Grant (n. 20441 to VR), by the GLOBALDOC Project - CUP H96J17000160002 approved with A.D. n. 9 from Puglia Region, financed under the Action Plan for Cohesion approved with Commission decision C (2016) 1417 to AGS. This research project was supported in part by the Apulian Regional Project “Medicina di Precisione” to AGS. AR was supported by the Wilhelm Sander-Stiftung (grant n. 2014.903.1).
JAM-A levels also correlated strongly with AURKA levels in MM patients. This finding may link JAM-A-mediated cell adhesion to MM resilience and drug resistance.20 Indeed, proteasome engulfment-derived proteotoxicity44 and invasiveness through epithelial-mesenchymal-transi- tion and cell adhesion45 are complex biological events that affect prognosis.46 We also demonstrated that the interac- tion between MMEC and MM-cells affects the expression of JAM-A and other fundamental molecules, such as TJP1 and LFA-1. This reciprocal “education” parallels the invasive behavior of the MM-cells towards the endothelial counter- part, instructing the vasculature to interact actively with the malignant cells, potentially driving their survival and drug resistance.47,48 In line with this, increased JAM-A endothelial levels correlated strongly with unfavorable and resistant MM stages such as high R-ISS disease stages and the risk of extramedullary development.
A network of interactions between JAM-A and a-eno- lase49 emphasizes the strong communication with the MM niche environment to allow persistence and sustaining pro- liferative signaling. Therefore, JAM-A may represent a key factor in the nurturing substrate50 supporting the evolution of MM. Moschetta et al.13 previously described the interder- pendency of endothelium and MM-cells: endothelial pro- genitor cell trafficking enhances MM progression, particu- larly at an early disease stage. Rajkumar et al. highlighted a progressive increase in BM angiogenesis along the spectrum of plasma cell disorders from MGUS to advanced MM.12 Integrating the prognostic relevance of JAM-A expressed by MMEC and our experimental data led us to propose JAM- A as a key player in coordinating the interactions with the MM milieu enabling a permissive BM ecosystem during the aggressive disease evolution from NDMM to RRMM.
Indeed, the anti-MM effect of blocking JAM-A also relies on a complex antiangiogenic effect, especially in critical transition phases of MM progression, such as the passage from MGUS to symptomatic MM and from responsive to drug-refractory disease, interfering with a main proangio- genic factor and with MM-cell proliferation. Our 2D and 3D models showed that, mechanistically, JAM-A drives MM-associated angiogenesis via a homophilic interaction and through identified downstream targets, namely FGF2, VEGF-A and PLG/ENO1, in the BM microenvironment. Moreover, the clinical impact demonstrated in a large cohort of consecutive individuals pinpoints the JAM-A axis
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