Halting the FGF/FGFR axis leads to antitumor activity in Waldenström macroglobulinemia by silencing MYD88

Abstract

The human fibroblast growth factor/fibroblast growth factor-receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström's Macroglobulinemia (WM). WM is still an incurable disease, and patients succumb due to disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR-signaling in NSC12-treated WM cells; unveiling a significant inhibition of MYD88 also confirmed at protein level. Importantly, the NSC12-dependent silencing of MYD88 was functionally active, as it led to inhibition of MYD88-driven pathways, such as BTK and SYK, as well as the MYD88-downstream target HCK. Of note, both canonical and non-canonical NFkB cascades were down-regulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3 and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.

Single-cell profiles reveal tumor cell heterogeneity and immunosuppressive microenvironment in Waldenström macroglobulinemia

“…Our understanding of the pathogenesis and immune escape mechanisms of WM is still limited [3]. The clinical onset of WM is often characterized by the development of anemia and progressive tumor infiltration, highlighting the importance of tumor infiltration in disease development and progression [4]. Genetic analyses have demonstrated recurrent mutations of the myeloid differentiation primary response-88 (MYD88) gene in more than 87.5% of WM patients in our lymphoma center of Blood Disease Hospital, CAMS [5].…”

Pentraxin 3 Inhibits the Angiogenic Potential of Multiple Myeloma Cells

“…Among the pro-angiogenic factors, Fibroblast Growth Factor 2 (FGF2) has been shown to play a relevant role in different tumor types, including MM [ 7 , 8 , 9 ], its blockade resulting in significant anti-tumor and anti-angiogenic activities [ 10 , 11 ]. Accordingly, the pattern recognition receptor Long Pentraxin 3 (PTX3), a secreted/stromal component of innate immunity able to bind and inactivate various members of the FGF family, including FGF2, has revealed potent anti-angiogenic and anti-tumor properties in different FGF-dependent tumors [ 12 , 13 , 14 , 15 , 16 , 17 ].…”

Exploring the Structural and Functional Diversity among FGF Signals: A Comparative Study of Human, Mouse, and Xenopus FGF Ligands in Embryonic Development and Cancer Pathogenesis

“…The four major signaling pathways activated by canonical FGFs include the RAS-MAPK, phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT, phospholipase Cγ/protein kinase C, and signal transducer and activator (STAT) pathways [10]. Additionally, canonical FGFs are key regulators of mesenchymal and epithelial signaling required for organogenesis [31].…”