FGF Trapping Inhibits Multiple Myeloma Growth through c-Myc Degradation–Induced Mitochondrial Oxidative Stress

Ronca, Roberto; Ghedini, Gaia C.; Maccarinelli, Federica; Sacco, Antonio; Locatelli, Silvia L.; Foglio, Eleonora; Taranto, Sara; Grillo, Elisabetta; Matarazzo, Sara; Castelli, Riccardo; Paganini, Giuseppe; Desantis, Vanessa; Cattane, Nadia; Cattaneo, Annamaria; Mor, Marco; Carlo‐Stella, Carmelo; Belotti, Angelo; Roccaro, Aldo M.; Presta, Marco; Giacomini, Arianna

doi:10.1158/0008-5472.can-19-2714

Cited by 41 publications

(38 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multiple myeloma is the world's second most common hematologic malignancy with high heterogeneity (Ronca et al, 2020). Currently, various prognostic models have been established to guide risk stratification and predict patient survival (Kyrtsonis et al, 2009), but few of them were incorporated into clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Super-Enhancer Associated Five-Gene Risk Score Model Predicts Overall Survival in Multiple Myeloma Patients

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Multiple myeloma (MM) is a malignant plasma cell tumor with high heterogeneity, characterized by anemia, hypercalcemia, renal failure, and lytic bone lesions. Although various powerful prognostic factors and models have been exploited, the development of more accurate prognosis and treatment for MM patients is still facing many challenges. Given the essential roles of super-enhancer (SE) associated genes in the tumorigenesis of MM, we tried to initially screen and identify the significant prognostic factors from SE associated genes in MM by the least absolute shrinkage and selection operator (Lasso) penalized Cox regression, univariate and multivariate Cox regression analysis using GSE24080 and GSE9782 datasets. Risk score model of five genes including CSGALNACT1, FAM53B, TAPBPL, REPIN1, and DDX11, was further constructed and the Kaplan-Meier (K-M) curves showed that the low-risk group seems to have better clinical outcome of survival compared to the high-risk group. Time-dependent receiver operating characteristic (ROC) curves presented the favorable performance of the model. An interactive nomogram consisting of the five-gene risk group and eleven clinical traits was established and identified by calibration curves. Therefore, the risk score model of SE associated five genes developed here could be used to predict the prognosis of MM patients, which may assist the clinical treatment of MM patients in the future.

show abstract

Section: Discussionmentioning

confidence: 99%

Super-Enhancer Associated Five-Gene Risk Score Model Predicts Overall Survival in Multiple Myeloma Patients

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…RNA was extracted from WM cell lines (BCWM.1; MWCL.1), as previously reported. 42,44,45 RNA samples were processed using WT PLUS Reagent Kit, according to manifacturer's protocol (Thermo Fisher Scientific, Waltham, MA, USA). Wide mRNA-transcriptome profiling was assessed using Clariom D Human array (Thermo Fisher Scientific, Waltham, MA, USA).…”

Section: Transcriptome Profilingmentioning

confidence: 99%

“…In vivo studies were performed as previously reported. 30,42,45 A detailed description is provided within the Supplemental file.…”

Section: Transcriptome Profilingmentioning

confidence: 99%

“…The human fibroblast growth factor/fibroblast growth factor-receptor (FGF/FGF-R) axis plays an essential role in a wide range of cellular processes, such as cell proliferation, differentiation, migration and survival, and its oncogenic role has been described both in solid tumors and hematologic malignancies, including multiple myeloma and Waldenström macroglobulinemia (WM). [1][2][3][4][5][6][7][8][9][10] WM is a low-grade lymphoproliferative disorder characterized by the presence of a lymphoplasmacytic infiltrate in the bone marrow; serum monoclonal immunoglobulin M; 11,12 and a somatic mutational profile involving MYD88 and CXCR4 that has been shown to supporting WM pathogenesis and disease progression. [13][14][15][16][17][18][19] Nevertheless, WM is still an incurable disease, and patients succumb due to disease progression.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Sacco

Federico

Giacomini

et al. 2021

Blood

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…In common with other pentraxins, the C -terminal portion of PTX3 includes the pentraxin-signature [ 17 ] whereas its unique N -terminal extension is responsible for binding to different members of the fibroblast growth factor (FGF) superfamily (including FGF2, FGF6, FGF8b, FGF10, and FGF17), thus preventing their interaction with all members of the FGFR family (FGFR1–4) [ 18 , 19 , 20 ]. Thus, PTX3 inhibits FGF-dependent responses, such as endothelial cell proliferation in vitro and angiogenesis in vivo [ 19 , 21 , 22 ], and exerts an oncosuppressive effect on FGF-dependent tumors, including multiple myeloma, melanoma, fibrosarcoma, lung, prostate, and bladder cancers [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. In a therapeutic perspective, these findings led to the identification of the PTX3-derived small molecule NSC12 as the first orally available FGF trap able to inhibit the activity of all the members of the canonical FGF family by preventing their binding to FGFR1, 2, 3, and 4 [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Long-Pentraxin 3 Affects Primary Cilium in Zebrafish Embryo and Cancer Cells via the FGF System

Guerra

Chiodelli

Tobia

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

Primary cilium drives the left-right asymmetry process during embryonic development. Moreover, its dysregulation contributes to cancer progression by affecting various signaling pathways. The fibroblast growth factor (FGF)/FGF receptor (FGFR) system modulates primary cilium length and plays a pivotal role in embryogenesis and tumor growth. Here, we investigated the impact of the natural FGF trap long-pentraxin 3 (PTX3) on the determination of primary cilium extension in zebrafish embryo and cancer cells. The results demonstrate that down modulation of the PTX3 orthologue ptx3b causes the shortening of primary cilium in zebrafish embryo in a FGF-dependent manner, leading to defects in the left-right asymmetry determination. Conversely, PTX3 upregulation causes the elongation of primary cilium in FGF-dependent cancer cells. Previous observations have identified the PTX3-derived small molecule NSC12 as an orally available FGF trap with anticancer effects on FGF-dependent tumors. In keeping with the non-redundant role of the FGF/FGR system in primary cilium length determination, NSC12 induces the elongation of primary cilium in FGF-dependent tumor cells, thus acting as a ciliogenic anticancer molecule in vitro and in vivo. Together, these findings demonstrate the ability of the natural FGF trap PTX3 to exert a modulatory effect on primary cilium in embryonic development and cancer. Moreover, they set the basis for the design of novel ciliogenic drugs with potential implications for the therapy of FGF-dependent tumors.

show abstract

FGF Trapping Inhibits Multiple Myeloma Growth through c-Myc Degradation–Induced Mitochondrial Oxidative Stress

Cited by 41 publications

References 62 publications

Super-Enhancer Associated Five-Gene Risk Score Model Predicts Overall Survival in Multiple Myeloma Patients

Super-Enhancer Associated Five-Gene Risk Score Model Predicts Overall Survival in Multiple Myeloma Patients

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

Long-Pentraxin 3 Affects Primary Cilium in Zebrafish Embryo and Cancer Cells via the FGF System

Contact Info

Product

Resources

About