Integrin alpha9 emerges as a key therapeutic target to reduce metastasis in rhabdomyosarcoma and neuroblastoma

Navarro, Natalia; Molist, Carla; Sansa-Girona, Julia; Zarzosa, Patricia; Gallo-Oller, Gabriel; Pons, Guillem; Magdaleno, Ainara; Guillén, Gabriela; Hladun, Raquel; Garrido, Marta; Segura, Miguel F.; Hontecillas-Prieto, Lourdes; Álava, Enrique de; Ponsati, Berta; Fernández‐Carneado, Jimena; Almazán-Moga, Ana; Vallès-Miret, Mariona; Farrera‐Sinfreu, Josep; Toledo, Josep Sánchez de; Moreno, Lucas; Gallego, Soledad; Roma, Josep

doi:10.1007/s00018-022-04557-y

Cited by 3 publications

(2 citation statements)

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“… 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 Despite the known association of neutrophil hyperactivation in stroke as well as in DVT, the contribution of neutrophil integrin α9 to the pathogenesis of DVT remains unknown. Previous studies by us and others have shown a key role of integrin α9 in the modulation of arterial thrombosis, 32 stroke, 34 , 43 rheumatoid arthritis, 62 , 63 cancer, 64 , 65 , 66 and vascular remodeling. 67 , 68 Here, using genetic and pharmacological approaches in combination with transcriptomics, pharmacogenomic profiling, and virtual screening, we uncovered a previously unknown pathway involving integrin α9 and VCAM-1 in promoting DVT.…”

Section: Discussionmentioning

confidence: 92%

Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT

Pandey,

Kaur,

Chorawala

et al. 2024

Blood Advances

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Venous thromboembolic events are significant contributors to morbidity and mortality in patients with stroke. Neutrophils are among the first cells in the blood to respond to stroke and are known to promote deep vein thrombosis (DVT). Integrin α9 is a transmembrane glycoprotein, highly expressed on neutrophils and stabilizes neutrophil adhesion to activated endothelium via vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, the causative role of neutrophil integrin α9 in post-stroke DVT remains unknown. Here, we found higher neutrophil integrin α9 and plasma VCAM-1 levels in humans and mice with stroke. Using mice with embolic stroke, we observed enhanced DVT severity in a novel model of post-stroke DVT. Neutrophil-specific integrin α9 deficient mice (α9fl/flMrp8Cre+/−) exhibited a significant reduction in post-stroke DVT severity along with decreased neutrophils and citrullinated histone H3 in thrombi. Unbiased transcriptomics indicated that α9/VCAM-1 interactions induced pathways related to neutrophil inflammation, exocytosis, NF-κB signaling, and chemotaxis. Mechanistic studies revealed that integrin α9/VCAM-1 interactions mediate neutrophil adhesion at the venous shear rate, promote neutrophil hyperactivation, increase phosphorylation of extracellular signal-regulated kinase (ERK), and induce endothelial cell apoptosis. Using pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin α9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in α9fl/flMrp8Cre+/− mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin α9. Collectively, we uncovered a previously unrecognized and critical pathway involving the α9/VCAM-1 axis in neutrophil hyperactivation and DVT.-

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Section: Discussionmentioning

confidence: 92%

Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT

Pandey,

Kaur,

Chorawala

et al. 2024

Blood Advances

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“…Another study conducted by Almacellas-Rabaiget et al examined the role of lysyl oxidase-like 2 (LOXL2), a regulator of tumor progression and metastasis, in orthotopic xenograft aRMS models that developed spontaneous lung metastasis attributed to LOXL2 overexpression (72). In one further study in which an experimental tail vein metastasis RMS mouse model was used, Navarro et al showed that Integrin alpha9 was essential for tumor dissemination, with reduction of metastatic formation by applying a synthetic peptide, RA08 (94). A preclinical study focusing on tumor microenvironment was conducted by Miyagaki et al, investigating the antitumor effects by suppressing lipid metabolism in an orthotopic xenograft mouse model (95).…”

Section: Tumorigenesismentioning

confidence: 99%

Contemporary preclinical mouse models for pediatric rhabdomyosarcoma: from bedside to bench to bedside

Martynov,

Dhaka,

Wilke

et al. 2024

Front. Oncol.

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BackgroundRhabdomyosarcoma (RMS) is the most common pediatric soft-tissue malignancy, characterized by high clinicalopathological and molecular heterogeneity. Preclinical in vivo models are essential for advancing our understanding of RMS oncobiology and developing novel treatment strategies. However, the diversity of scholarly data on preclinical RMS studies may challenge scientists and clinicians. Hence, we performed a systematic literature survey of contemporary RMS mouse models to characterize their phenotypes and assess their translational relevance.MethodsWe identified papers published between 01/07/2018 and 01/07/2023 by searching PubMed and Web of Science databases.ResultsOut of 713 records screened, 118 studies (26.9%) were included in the qualitative synthesis. Cell line-derived xenografts (CDX) were the most commonly utilized (n = 75, 63.6%), followed by patient-derived xenografts (PDX) and syngeneic models, each accounting for 11.9% (n = 14), and genetically engineered mouse models (GEMM) (n = 7, 5.9%). Combinations of different model categories were reported in 5.9% (n = 7) of studies. One study employed a virus-induced RMS model. Overall, 40.0% (n = 30) of the studies utilizing CDX models established alveolar RMS (aRMS), while 38.7% (n = 29) were embryonal phenotypes (eRMS). There were 20.0% (n = 15) of studies that involved a combination of both aRMS and eRMS subtypes. In one study (1.3%), the RMS phenotype was spindle cell/sclerosing. Subcutaneous xenografts (n = 66, 55.9%) were more frequently used compared to orthotopic models (n = 29, 24.6%). Notably, none of the employed cell lines were derived from primary untreated tumors. Only a minority of studies investigated disseminated RMS phenotypes (n = 16, 13.6%). The utilization areas of RMS models included testing drugs (n = 64, 54.2%), studying tumorigenesis (n = 56, 47.5%), tumor modeling (n = 19, 16.1%), imaging (n = 9, 7.6%), radiotherapy (n = 6, 5.1%), long-term effects related to radiotherapy (n = 3, 2.5%), and investigating biomarkers (n = 1, 0.8%). Notably, no preclinical studies focused on surgery.ConclusionsThis up-to-date review highlights the need for mouse models with dissemination phenotypes and cell lines from primary untreated tumors. Furthermore, efforts should be directed towards underexplored areas such as surgery, radiotherapy, and biomarkers.

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Loss of p53 epigenetically modulates epithelial to mesenchymal transition in colorectal cancer

Sharma,

Rani,

Mahesh

et al. 2024

Translational Oncology

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Integrin alpha9 emerges as a key therapeutic target to reduce metastasis in rhabdomyosarcoma and neuroblastoma

Cited by 3 publications

References 50 publications

Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT

Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT

Contemporary preclinical mouse models for pediatric rhabdomyosarcoma: from bedside to bench to bedside

Loss of p53 epigenetically modulates epithelial to mesenchymal transition in colorectal cancer

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