Loss of tumor suppressor WWOX accelerates pancreatic cancer development through promotion of TGFβ/BMP2 signaling

Husanie, Hussam; Abu-Remaileh, Muhannad; Maroun, Kian; Abu-Tair, Lina; Safadi, Hazem; Atlan, Karine; Golan, Talia; Aqeilan, Rami I.

doi:10.1038/s41419-022-05519-9

Cited by 8 publications

(5 citation statements)

References 51 publications

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“…From the 49 somatic SVs detected in COLO829-lifted (45 TP and 4 FN), 35 SVs overlap with 26 known genes, of which 25 are related to cancer. Some examples are FHIT (near a fragile site), tumor suppressors ITIH5, MAGI2, PTEN, WWOX, and cell-proliferation control gene TMX3 (Bellon et al 2021; Cao et al 2020; Yehia et al 2023; Husanie et al 2022; Zhang et al 2019).…”

Section: Resultsmentioning

confidence: 99%

“…B) IGV screenshot of an SV that was labeled as FN according to the benchmark by Valle-Inclan et al Our analysis calls removed thee SVs due to lack of evidence in all samples (Supplementary Table 13)Overall, the approach of incorporating alignment to CHM13-T2T followed by liftover analysis eliminated all FP somatic SV calls for COLO829. Such a reduction in FP has important impacts suppressors ITIH5, MAGI2, PTEN, WWOX, and cell-proliferation control gene TMX3(Bellon et al 2021;Cao et al 2020;Yehia et al 2023;Husanie et al 2022;Zhang et al 2019).…”

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confidence: 99%

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The benefit of a complete reference genome for cancer structural variant analysis

Paulin,

Fan,

O’Neill

et al. 2024

Preprint

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The complexities of cancer genomes are becoming more easily interpreted due to advancements in sequencing technologies and improved bioinformatic analysis. Structural variants (SVs) represent an important subset of somatic events in tumors. While detection of SVs has been markedly improved by the development of long-read sequencing, somatic variant identification and annotation remains challenging. We hypothesized that use of a completed human reference genome (CHM13-T2T) would improve somatic SV calling. Our findings in a tumour/normal matched benchmark sample and two patient samples show that the CHM13-T2T improves SV detection and prioritization accuracy compared to GRCh38, with a notable reduction in false positive calls. We also overcame the lack of annotation resources for CHM13-T2T by lifting over CHM13-T2T-aligned reads to the GRCh38 genome, therefore combining both improved alignment and advanced annotations. In this process, we assessed the current SV benchmark set for COLO829/COLO829BL across four replicates sequenced at different centers with different long-read technologies. We discovered instability of this cell line across these replicates; 346 SVs (1.13%) were only discoverable in a single replicate. We identify 49 somatic SVs, which appear to be stable as they are consistently present across the four replicates. As such, we propose this consensus set as an updated benchmark for somatic SV calling and include both GRCh38 and CHM13-T2T coordinates in our benchmark. The benchmark is available at: 10.5281/zenodo.10819636 Our work demonstrates new approaches to optimize somatic SV prioritization in cancer with potential improvements in other genetic diseases.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

The benefit of a complete reference genome for cancer structural variant analysis

Paulin,

Fan,

O’Neill

et al. 2024

Preprint

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“…The location of WWOX in a chromosomal region that is frequently altered in various cancers has prompted research to determine its role in carcinogenesis. Moreover, literature data on in vivo studies suggest that WWOX in murine models has a crucial role in biological processes such as growth or metabolism, and that its loss leads to enhanced cancer stemness [ 69 , 70 ]. Recent molecular and clinical analyses of WWOX functions have emphasized its role in the modulation of signaling pathways related to cancer promotion, metabolism, CNS development, and neurological diseases [ 10 , 70 , 71 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, literature data on in vivo studies suggest that WWOX in murine models has a crucial role in biological processes such as growth or metabolism, and that its loss leads to enhanced cancer stemness [ 69 , 70 ]. Recent molecular and clinical analyses of WWOX functions have emphasized its role in the modulation of signaling pathways related to cancer promotion, metabolism, CNS development, and neurological diseases [ 10 , 70 , 71 , 72 ]. Furthermore, our previous in silico study proved that the WWOX is associated with complex protein networks, highlighting its direct and indirect function in maintaining cell homeostasis in GBM [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Antineoplastic Nature of WWOX in Glioblastoma Is Mainly a Consequence of Reduced Cell Viability and Invasion

Kałuzińska

Kośla

Kołat

et al. 2023

Biology

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Following the discovery of WWOX, research has moved in many directions, including the role of this putative tumor suppressor in the central nervous system and related diseases. The task of determining the nature of WWOX in glioblastoma (GBM) is still considered to be at the initial stage; however, the influence of this gene on the GBM malignant phenotype has already been reported. Because most of the available in vitro research does not consider several cellular GBM models or a wide range of investigated biological assays, the present study aimed to determine the main processes by which WWOX exhibits anticancer properties in GBM, while taking into account the phenotypic heterogeneity between cell lines. Ectopic WWOX overexpression was studied in T98G, DBTRG-05MG, U251MG, and U87MG cell lines that were compared with the use of assays investigating cell viability, proliferation, apoptosis, adhesion, clonogenicity, three-dimensional and anchorage-independent growth, and invasiveness. Observations presenting the antineoplastic properties of WWOX were consistent for T98G, U251MG, and U87MG. Increased proliferation and tumor growth were noted in WWOX-overexpressing DBTRG-05MG cells. A possible explanation for this, arrived at via bioinformatics tools, was linked to the TARDBP transcription factor and expression differences of USP25 and CPNE2 that regulate EGFR surface abundance. Collectively, and despite various cell line-specific circumstances, WWOX exhibits its anticancer nature mainly via a reduction of cell viability and invasiveness of glioblastoma.

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“…For generating WWOX overexpression in DKO yBM cells, cells were infected with lentiviral vector containing the wild type WWOX and selected with 2 mg/mL G418 (Gibco: 11811031)(36)…”

Section: Methodsmentioning

confidence: 99%

WWOX promotes osteosarcoma development via upregulation of Myc

Akkawi¹,

Monin²,

Diment³

et al. 2023

Preprint

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Osteosarcoma (OS) is an aggressive bone tumor that primarily affects children and adolescents. This malignant tumor is highly aggressive, associated with poor clinical outcomes, and metastasizes mainly to the lungs. Due to its rarity and biological heterogeneity, limited studies of its molecular basis exist, thus hindering the development of effective therapies. WW domain-containing oxidoreductase (WWOX) spans one of the most active and common fragile sites that is frequently altered in human OS. The combined deletion of Wwox and Trp53 using Osterix1-Cre transgenic mice has been shown to accelerate OS development. In this study, we generated a traceable OS mouse model, SKO-Trp53 or DKO-Wwox/Trp53, expressing a tdTomato reporter. By tracking tomato expression at different time points, we detected the early presence of tdTomato-positive cells in the bone marrow (BM) mesenchymal stem cells (MSCs) of non-OS bearing mice, young BM (yBM). We found that DKO yBM cells, but not SKO yBM cells, exhibited tumorigenic traits both in vitro and in vivo. Molecular and cellular characterization of these DKO yBM cells revealed their resemblance to OS tumor cells. Interestingly, one of the early observed transcriptomic changes in DKO yBM was the upregulation of Myc and its target genes compared to SKO yBM cells. As a prototype target, we further demonstrated the upregulation of MCM7, a known Myc target, in DKO yBM relative to SKO yBM. Therapeutic targeting of MCM7 using simvastatin (SVA) resulted in attenuation of OS tumor growth. Our findings reveal BM-MSCs as a platform to study OS, and reveal Myc and its targets as early molecular events during osteosarcomagenesis.

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Loss of tumor suppressor WWOX accelerates pancreatic cancer development through promotion of TGFβ/BMP2 signaling

Cited by 8 publications

References 51 publications

The benefit of a complete reference genome for cancer structural variant analysis

The benefit of a complete reference genome for cancer structural variant analysis

Antineoplastic Nature of WWOX in Glioblastoma Is Mainly a Consequence of Reduced Cell Viability and Invasion

WWOX promotes osteosarcoma development via upregulation of Myc

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