Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma

Marko, Tracy A.; Shamsan, Ghaidan A.; Edwards, Elizabeth N; Hazelton, Paige E; Rathe, Susan K.; Cornax, Ingrid; Overn, Paula; Varshney, Jyotika; Diessner, Brandon J.; Moriarity, Branden S.; O’Sullivan, M. Gerard; Odde, David J.; Largaespada, David A.

doi:10.1038/srep39059

Cited by 34 publications

(28 citation statements)

References 29 publications

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“…srGAP3 expression is decreased in the majority of breast cancer cell lines, and loss of srGAP3 leads to both anchorage-independent growth and increased cell invasion and/or migration; these changes are GAP dependent, suggesting that srGAP3 acts as a tumor suppressor through its ability to inactivate Rac (Lahoz and Hall, 2013). Similar phenotypes are observed upon srGAP2 loss in osteosarcomas (Marko et al, 2016). Separating correlation from causation in the numerous clinical studies that have been reported will be challenging, but these studies clearly implicate srGAPs in a wide range of human disease.…”

Section: Box 2 Srgaps In Non-neuronal Diseasementioning

confidence: 78%

Mind the (sr)GAP – roles of Slit–Robo GAPs in neurons, brains and beyond

Lucas

Hardin

2017

Journal of Cell Science

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The Slit-Robo GTPase-activating proteins (srGAPs) were first identified as potential Slit-Robo effectors that influence growth cone guidance. Given their N-terminal F-BAR, central GAP and C-terminal SH3 domains, srGAPs have the potential to affect membrane dynamics, Rho family GTPase activity and other binding partners. Recent research has clarified how srGAP family members act in distinct ways at the cell membrane, and has expanded our understanding of the roles of srGAPs in neuronal and non-neuronal cells. Gene duplication of the human-specific paralog of srGAP2 has resulted in srGAP2 family proteins that may have increased the density of dendritic spines and promoted neoteny of the human brain during crucial periods of human evolution, underscoring the importance of srGAPs in the unique sculpting of the human brain. Importantly, srGAPs also play roles outside of the nervous system, including during contact inhibition of cell movement and in establishing and maintaining cell adhesions in epithelia. Changes in srGAP expression may contribute to neurodevelopmental disorders, cancer metastasis and inflammation. As discussed in this Review, much remains to be discovered about how this interesting family of proteins functions in a diverse set of processes in metazoans and the functional roles srGAPs play in human disease.

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Section: Box 2 Srgaps In Non-neuronal Diseasementioning

confidence: 78%

Mind the (sr)GAP – roles of Slit–Robo GAPs in neurons, brains and beyond

Lucas

Hardin

2017

Journal of Cell Science

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“…Notably, while down-regulation of SrGAP2 contributes to a more aggressive phenotype, most likely by enhancing cell migration, down-regulation of srGAP3 promotes Rac1-dependent, anchorage-independent cell growth (49,50). …”

Section: Emerging Paradigms In Rho Gtpase Hyperactivation In Cancermentioning

confidence: 99%

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

2017

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Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer, and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors (GEFs), defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase activating proteins (GAPs) also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anti-cancer agents, including targeted therapies, as well as to the suppression of anti-tumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting.

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“…Stable shRNA knockdown lines were established via puromycin selection at 1 μg/mL. Overexpression vectors were generated using the human SEMA4C cDNA sequence (#40035253, Dharmacon) and vectors/cell lines were established using previously described methodology [20, 21].…”

Section: Methodsmentioning

confidence: 99%

“…Wound healing assays were performed as previously described [20]. Briefly, 1 × 10 4 cells were plated into a removable 2-well silicone culture insert which generated a defined cell-free gap (ibidi).…”

Section: Methodsmentioning

confidence: 99%

SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis

Smeester

Slipek

Pomeroy

et al. 2019

Preprint

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47Semaphorins, specifically type IV, are important regulators of axonal guidance and 48 have been increasingly implicated in poor prognoses in a number of different solid 49 cancers. In conjunction with their cognate PLXNB family receptors, type IV members have 50 been increasingly shown to mediate oncogenic functions necessary for tumor 51 development and malignant spread. In this study, we investigated the role of semaphorin 52 4C (SEMA4C) in osteosarcoma growth, progression, and metastasis. We investigated 53 the expression and localization of SEMA4C in primary osteosarcoma patient tissues and 54 its tumorigenic functions in these malignancies. We demonstrate that overexpression of 55 SEMA4C promotes properties of cellular transformation, while RNAi knockdown of 56 SEMA4C promotes adhesion and reduces cellular proliferation, colony formation, 57 migration, wound healing, tumor growth, and lung metastasis. These phenotypic changes 58 were accompanied by reductions in activated AKT signaling, G1 cell cycle delay, and 59 decreases in expression of mesenchymal marker genes SNAI1, SNAI2, and TWIST1. 60Lastly, monoclonal antibody blockade of SEMA4C in vitro mirrored that of the genetic 61 studies. Together, our results indicate a multi-dimensional oncogenic role for SEMA4C in 62 metastatic osteosarcoma and more importantly that SEMA4C has actionable clinical 63 potential. 64 65 Introduction 66Osteosarcoma is a malignant, primarily pediatric tumor, of the growing long bones 67 with peak incidence in the second decade of life [1]. Derived from mesenchymal origins 68 in the pre-osteoblastic lineage, osteosarcomas arise from the failure of osteoblasts to 69 differentiate into mature bone-building cells [2]. Osteosarcomas are commonly typified by 70 their heterogeneity, genomic instability, and frequency of systemic metastasis primarily 71 to the lungs [3, 4]. Despite advances in chemotherapy regimens and surgical resection, 72 survival rates for patients with osteosarcoma have remained stagnant for more than four 73 decades [5]. The complex nature of osteosarcoma presents unique difficulties with 74 respect to elucidating novel therapeutic targets and identifying treatment strategies that 75 may prove most effective, particularly across individual patients. Given this, it is critically 76 important to better understand not only the mechanisms specific to osteosarcoma 77 development and progression, but most importantly metastasis, in order to develop better 78 treatment options for patients with this devastating disease. 79 Semaphorins are a family of membrane-bound and soluble proteins that modulate 80 a whole host of cellular functions including differentiation, cytoskeletal rearrangement, 81 and motility [6]. Interestingly, semaphorin family members have been reported to mediate 82 many hallmarks of cancer including cellular proliferation, angiogenesis, and immune 83 escape [7-9]. Recent evidence from studies of the SEMA4-PLXNB family of axonal 84 guidance molecules in normal bone cells suggests that osteoclastic exp...

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Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma

Cited by 34 publications

References 29 publications

Mind the (sr)GAP – roles of Slit–Robo GAPs in neurons, brains and beyond

Mind the (sr)GAP – roles of Slit–Robo GAPs in neurons, brains and beyond

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis

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