Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation

Zeng, Hanlin; Jorapur, Aparna; Shain, A. Hunter; Lang, Ursula E.; Torres, Rodrigo; Zhang, Yuntian; McNeal, Andrew S.; Botton, Thomas; Lin, Jue; Donne, Matthew; Bastian, Ingmar N.; Yu, Richard; North, Jeffrey P.; Pincus, Laura B.; Ruben, Beth S.; Joseph, Nancy M.; Yeh, Iwei; Bastian, Boris C.; Judson, Robert L.

doi:10.1016/j.ccell.2018.05.014

Cited by 108 publications

(138 citation statements)

References 70 publications

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“…Phase images were analyzed using application specific software modules in the HStudio software. The metastatic 1205Lu line demonstrated significantly increased motility over the nonmetastatic WM793 line with as few as 4 h of imaging, consistent with previous reports (29). 1A) (29).…”

Section: Dhc Analysis Of Proliferation and Motilitysupporting

confidence: 91%

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Evaluation of holographic imaging cytometer holomonitor M4® motility applications

Zhang

Judson

2018

Cytometry Pt A

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Digital holographic cytometry (DHC) and other methods of quantitative phase imaging permit extended time-lapse imaging of mammalian cells in the absence of induced cellular toxicity. Manufactured DHC platforms equipped with semi-automated image acquisition, segmentation, and analysis software packages (or modules) for assessing cell behavior are now commercially available. When housed in mammalian cell incubators these cytometers offer the potential to monitor and quantify a range of cellular behaviors without disrupting routine culture. Realization of this potential requires validation against established standards. Two proprietary software modules for assessing cellular motility available using the HoloMonitor M4 DHC platform were evaluated on human melanoma cells lines with known relative motility and metastatic potential. One such software package, the Track Cells module, was run during routine culture. In addition, the Wound Healing module was conducted in parallel with established transwell migration and invasion assays. Each module was evaluated for reproducibility and correlation to established assays. Both software modules reliably recorded increased cellular motility in the metastatic 1205Lu line as compared with the non-metastatic WM793 line. In a direct comparison of the two propriety DHC software modules and two established transwell assays, the relative cell motilities were well correlated. The granularity of data provided by the Track Cells module permitted the additional identification of rare hyper-motile cells in the metastatic population and the distinction of motility from division associated displacement. The two HoloMonitor M4 DHC proprietary software modules for assessing cellular motility yielded reproducible results that were well-correlated with established standards.

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Section: Dhc Analysis Of Proliferation and Motilitysupporting

confidence: 91%

“…Previous studies have demonstrated that the WM793 line proliferates more rapidly and is less motile as compared with the 1205Lu line (29). Previous studies have demonstrated that the WM793 line proliferates more rapidly and is less motile as compared with the 1205Lu line (29).…”

Section: Dhc Analysis Of Proliferation and Motilitymentioning

confidence: 99%

Evaluation of holographic imaging cytometer holomonitor M4® motility applications

Zhang

Judson

2018

Cytometry Pt A

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“…In contrast, the phenotype of invasive melanoma was associated with multiple aberrations, typically biallelic inactivation of CDKN2A . Functional data corroborate this association, as CDKN2A deletions, engineered into primary human melanocytes, confer migratory, invasive, and metastatic phenotypes (Zeng et al, 2018 [this issue of Cancer Cell ]).…”

Section: Discussionmentioning

confidence: 76%

Genomic and Transcriptomic Analysis Reveals Incremental Disruption of Key Signaling Pathways during Melanoma Evolution

et al. 2018

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We elucidated genomic and transcriptomic changes that accompany the evolution of melanoma from pre-malignant lesions by sequencing DNA and RNA from primary melanomas and their adjacent precursors, as well as matched primary tumors and regional metastases. In total, we analyzed 230 histopathologically distinct areas of melanocytic neoplasia from 82 patients. Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas. UV radiation-induced point mutations steadily increased until melanoma invasion, at which point copy-number alterations also became prevalent.

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“…To date, studies on molecular mechanisms of melanoma mainly focus on protein‐coding genes, such as NRAS , MTOR , CDKN2A , and BRAF . However, the initiation and progression of melanoma could not be fully explained by protein‐coding genes .…”

Section: Introductionmentioning

confidence: 99%

Increased expression of long noncoding RNA GAS6‐AS2 promotes proliferation and inhibits apoptosis of melanoma cells via upregulating GAS6 expression

et al. 2019

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Long noncoding RNAs (lncRNAs) are frequently aberrantly expressed and involved in many cancers, including melanoma. GAS6‐AS2 was a recently identified cancer‐related lncRNA. However, the expression, roles, and functional mechanisms of GAS6‐AS2 in melanoma remain unknown. In this study, we found that lncRNA GAS6‐AS2 is significantly elevated in melanoma tissues and cells. Elevated expression of GAS6‐AS2 is positively correlated with advanced stages and poor prognosis in melanoma. Functional assays demonstrated that ectopic expression of GAS6‐AS2 promotes proliferation and inhibits apoptosis of melanoma cells. In contrast, knockdown of GAS6‐AS2 inhibits proliferation and promotes apoptosis of melanoma cells. Furthermore, in vivo functional assays showed that GAS6‐AS2 promotes melanoma xenograft growth. Mechanistically, we found that GAS6‐AS2 upregulates GAS6 expression, promotes GAS6 secretion, and activates AXL/AKT/ERK signals. The expression of GAS6 was positively correlated with that of GAS6‐AS2 in melanoma tissues. In addition, deficiency of GAS6 reverses the biological roles of GAS6‐AS2 overexpression in melanoma cell proliferation and apoptosis. Collectively, our data identified GAS6‐AS2 as an oncogenic lncRNA in melanoma via activation of GAS6/AXL/AKT/ERK signals. Our data suggested that GAS6‐AS2 may be a novel potential prognostic biomarker and therapeutic target for melanoma.

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Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation

Cited by 108 publications

References 70 publications

Evaluation of holographic imaging cytometer holomonitor M4® motility applications

Evaluation of holographic imaging cytometer holomonitor M4® motility applications

Genomic and Transcriptomic Analysis Reveals Incremental Disruption of Key Signaling Pathways during Melanoma Evolution

Increased expression of long noncoding RNA GAS6‐AS2 promotes proliferation and inhibits apoptosis of melanoma cells via upregulating GAS6 expression

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