Metastasis in an orthotopic murine model of melanoma is independent of RAS/RAF mutation

Rozenberg, Gabriela I.; Monahan, Kimberly B.; Torrice, Chad; Sharpless, Norman E.

doi:10.1097/cmr.0b013e328336ee17

Cited by 33 publications

(28 citation statements)

References 46 publications

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“…Similarly, Rozenberg et al discovered overexpression of NEDD9 in metastatic melanoma cells in a murine model; however, interestingly, they also stated that NEDD9 lentiviral overexpression did not confer a metastatic ability on non-metastatic primary cells (15). This result supports the hypothesis that NEDD9 overexpression alone is not sufficient for tumorigenesis and invasiveness, but rather cooperation with other mechanisms impairing either checkpoints or apoptosis is required.…”

Section: Discussionsupporting

confidence: 74%

Significance of serum neural precursor cell‑expressed developmentally downregulated protein 9 in melanoma

et al. 2017

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Abstract. Neural precursor cell-expressed developmentally downregulated protein 9 (NEDD9) is a promoter for various cellular functions that result in tumorigenesis. The aim of the present study was to analyse the serum levels of NEDD9 in melanoma patients in order to evaluate its prognostic, predictive and diagnostic value. Data from 112 melanoma patients were retrospectively analyzed and ELISA assays were used to measure serum NEDD9 concentration. The median serum NEDD9 levels of the patients were significantly higher compared with those of the controls. Serum NEDD9 was not found to be associated with any of the clinicopathological parameters, and was also not found to be prognostic for survival in melanoma. Therefore, serum NEDD9 may be of diagnostic value in melanoma, but its usefulness in prognosis remains controversial. The important role of NEDD9 in tumor angiogenesis necessitates efforts to elucidate its interactions with the tumor microenvironment and its potential as a therapeutic target for malignancies. IntroductionThe Crk-associated substrate (Cas) family comprises four non-catalytic scaffolding proteins (NEDD9/HEF1/CAS-L, BCAR1/p130Cas, EFS/Sin, and HEPL/CASS4) that mediate the cell cycle, survival, migration/chemotaxis, apoptosis, differentiation and cell attachment (1-6). The Cas proteins have been thoroughly investigated, and even mildly overexpressed levels of these proteins have been found to be correlated with poor survival, resistance to chemotherapy and metastasis in malignancies such as melanoma, lung cancer, glioblastoma, and breast cancer. These proteins have not only been associated with cancer, but they have also been reported to be associated with other non-malignant conditions, including polycystic kidney disease (7).Neural precursor cell-expressed developmentally downregulated protein (NEDD9) interacts with novel SH2-containing protein family scaffold proteins and the adaptor proteins SHC and GRB2 via its C-terminal domain, and mediates the communication between receptor tyrosine kinases and integrins, so that receptors, such as T-cell, B-cell and integrin receptors, send upstream activation signals. Subsequently, focal adhesion kinase (FAK) and the Src and ABL families of kinases are activated and they, in turn, phosphorylate NEDD9 substrate domain even more extensively, which provides multiple binding sites, i.e., Y189, Y317 and Y279, for downstream effectors. FAK phosphorylation of the DYDY motif in the NEDD9 C-terminal generates a binding site for Src kinase, which enables NEDD9 to operate in migration and other signaling functions (7). Furthermore, Y189 phosphorylation by FAK and Src kinases is involved in focal adhesion. Aurora-A kinase phosphorylates S296; thus, proteasomal degradation of NEDD9 ensues, and cell dissemination and the cell cycle are regulated.NEDD9 is not only activated by FAK and Src kinases, but also maintains incessant activation of these kinases. NEDD9 connects tumor growth factor-β/SMAD and Rho-actin-SRF signals, thus participating in tumorigenesis by coord...

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Section: Discussionsupporting

confidence: 74%

Significance of serum neural precursor cell‑expressed developmentally downregulated protein 9 in melanoma

et al. 2017

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“…However, in pancreatic progenitor cells, decrease of CTGF protein repressed the phosphorylated activity of AKT on S473 and T308, but exerted slightly influence on ERK1 activity. Although Nedd9 interference has been reported to decrease downstream activation of ras signaling, including ERK1/24445 and CDK19, which is found to be involved in extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK)46, knock-downs of Nedd9 and CDK19 exert a little effect on ERK phosphorylation in pancreatic progenitor cells. IGF1 interference also did not affect the AKT and ERK1/2 activity.…”

Section: Discussionmentioning

confidence: 99%

miR-18a counteracts AKT and ERK activation to inhibit the proliferation of pancreatic progenitor cells

Zhang

et al. 2017

Sci Rep

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Activation of endogenous stem/progenitor cells to repair injured tissues is an ideal option for disease treatment. However, adult pancreatic progenitor cells remain in a quiescent state in vivo. Thus, it is difficult to stimulate proliferation and differentiation in these progenitor cells, and the cause remains elusive. miR-17-92 cluster miRNAs are highly conserved in mammals and are expressed in multiple tissue stem/progenitor cells, but their role in pancreatic progenitor cells are less well known. In the present study, we demonstrate that miR-18a, but not the other members of the miR-17-92 gene cluster, inhibits the proliferation of pancreatic progenitor cells in vitro and ex vivo. miR-18a inhibits proliferation of adult pancreatic progenitor cells through arresting the cell cycle at G1 stage, indicating that miR-18a plays a role in keeping the adult pancreatic progenitor cells in quiescence. miR-18a inhibits pancreatic progenitor proliferation by targeting the gene expressions of connective tissue growth factor (CTGF), neural precursor cell expressed, developmentally down-regulated 9 (Nedd9), and cyclin dependent kinase 19 (CDK19), as well as by suppressing activation of the proliferation-related signaling pathways phosphatidylinositol 3-kinase–protein kinase B (PI3K/AKT) and extracellular signal-regulated kinase (ERK).

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“…NEDD9 overexpression by itself failed to increase melanoma metastatic potential, but in conjunction with RAS overexpression resulted in enhanced invasion in Boyden Chamber by 3.4-fold, and significantly increased the number of metastases in mouse xenograft models [88]. In concordance with these results, Rozenberg et al used an in vivo mouse model of metastasis to show that metastatic melanoma cell lines have high NEDD9 expression, but that NEDD9 lentiviral transfection and overexpression did not confer metastatic potential on non-metastatic cells [89]. These data are compatible with the observations in mammary cancer models, discussed above, indicating that NEDD9 overexpression is only pro-tumorigenic in the context of other lesions that remove checkpoints or reduce apoptosis.…”

Section: Altered Nedd9 Expression In Cancermentioning

confidence: 96%

Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

Shagisultanova

Gaponova

Gabbasov

et al. 2015

Gene

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Cancer progression requires a significant reprogramming of cellular signaling to support the essential tumor-specific processes that include hyperproliferation, invasion (for solid tumors) and survival of metastatic colonies. NEDD9 (also known as CasL and HEF1) encodes a multi-domain scaffolding protein that assembles signaling complexes regulating multiple cellular processes relevant to cancer. These include responsiveness to signals emanating from the T and B cell receptors, integrins, chemokine receptors, and receptor tyrosine kinases, as well as cytoplasmic oncogenes such as BCR-ABL and FAK- and SRC-family kinases. Downstream, NEDD9 regulation of partners including CRKL, WAVE, PI3K/AKT, ERK, E-cadherin, Aurora-A (AURKA), HDAC6, and others allow NEDD9 to influence functions as pleiotropic as migration, invasion, survival, ciliary resorption, and mitosis. In this review, we summarize a growing body of preclinical and clinical data that indicate that while NEDD9 is itself non-oncogenic, changes in expression of NEDD9 (most commonly elevation of expression) are common features of tumors, and directly impact tumor aggressiveness, metastasis, and response to at least some targeted agents inhibiting NEDD9-interacting proteins. These data strongly support the relevance of further development of NEDD9 as a biomarker for therapeutic resistance. Finally, we briefly discuss emerging evidence supporting involvement of NEDD9 in additional pathological conditions, including stroke and polycystic kidney disease.

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Metastasis in an orthotopic murine model of melanoma is independent of RAS/RAF mutation

Cited by 33 publications

References 46 publications

Significance of serum neural precursor cell‑expressed developmentally downregulated protein 9 in melanoma

Significance of serum neural precursor cell‑expressed developmentally downregulated protein 9 in melanoma

miR-18a counteracts AKT and ERK activation to inhibit the proliferation of pancreatic progenitor cells

Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

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