ADAM9 Promotes Lung Cancer Metastases to Brain by a Plasminogen Activator-Based Pathway

Lin, Chen; Chen, Hung Jen; Huang, Chiung-Hua; Lai, Liang‐Chuan; Lu, Tzu-Pin; Tseng, Guan Chin; Kuo, Ting Ting; Kuok, Qian Yu; Hsu, Jennifer L.; Sung, Shian Ying; Hung, Mien Chie; Sher, Yuh Pyng

doi:10.1158/0008-5472.can-13-2995

Cited by 70 publications

(78 citation statements)

References 47 publications

(45 reference statements)

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“…injection into nude mice (36). In agreement, overexpression of ADAM9 in lung cancer cells resulted in both brain and lung metastases, whereas mock-transfected cells only colonized the lungs (37,38). All these results are in accordance with clinical observations indicating that expression of ADAM9 was correlated with shortened survival and poor outcome of cancer patients and associated with the occurrence of distant metastases (39)(40)(41).…”

Section: Discussionsupporting

confidence: 74%

Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell–derived ADAM9

Mammadova‐Bach¹,

Zigrino²,

Brucker³

et al. 2016

JCI Insight

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Section: Discussionsupporting

confidence: 74%

Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell–derived ADAM9

Mammadova‐Bach¹,

Zigrino²,

Brucker³

et al. 2016

JCI Insight

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“…S3). For example, ADAM9 is implicated in lung cancer and is a risk marker for distant metastases (24). EFNB2, a receptor tyrosine kinase (TK), also cycled strongly and may have prognostic significance in both small cell lung cancer and nonpulmonary cancers (25).…”

Section: Resultsmentioning

confidence: 99%

CYCLOPS reveals human transcriptional rhythms in health and disease

Anafi

Francey

Hogenesch

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

197

242

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Circadian rhythms modulate many aspects of physiology. Knowledge of the molecular basis of these rhythms has exploded in the last 20 years. However, most of these data are from model organisms, and translation to clinical practice has been limited. Here, we present an approach to identify molecular rhythms in humans from thousands of unordered expression measurements. Our algorithm, cyclic ordering by periodic structure (CYCLOPS), uses evolutionary conservation and machine learning to identify elliptical structure in high-dimensional data. From this structure, CYCLOPS estimates the phase of each sample. We validated CYCLOPS using temporally ordered mouse and human data and demonstrated its consistency on human data from two independent research sites. We used this approach to identify rhythmic transcripts in human liver and lung, including hundreds of drug targets and disease genes. Importantly, for many genes, the circadian variation in expression exceeded variation from genetic and other environmental factors. We also analyzed hepatocellular carcinoma samples and show these solid tumors maintain circadian function but with aberrant output. Finally, to show how this method can catalyze medical translation, we show that dosage time can temporally segregate efficacy from dose-limiting toxicity of streptozocin, a chemotherapeutic drug. In sum, these data show the power of CYCLOPS and temporal reconstruction in bridging basic circadian research and clinical medicine.gene expression | biological rhythms | machine learning | autoencoder | circadian rhythms C ircadian rhythms are nearly ubiquitous in nature. In animals, much of physiology and behavior is under circadian control. Body temperature, hormonal rhythms, blood pressure, and locomotor activity are just a few of the processes displaying daily rhythms. In circadian model systems (e.g., cyanobacteria, Neurospora, Arabidopsis, Drosophila, and mice), high-resolution time sampling is straightforward, and experiments show that a substantial fraction of the transcriptome is under clock control. For example, in mice, a majority of genes are clock regulated in at least 1 of 12 different organs (1).Circadian rhythms are also critical for humans. Shift work-induced circadian misalignment is associated with higher rates of metabolic, cardiovascular, and neoplastic disease. Clinical experience suggests time of day can have a marked effect on disease severity (2-4). Indeed, the majority of the best-selling prescription drugs and World Health Organization essential medicines target molecules that oscillate in mice (1). However, translation of these findings to clinical medicine remains slow. How does human molecular physiology change with circadian time? In mice, and presumably humans, circadian output genes are markedly different in each tissue. Obviously, repeated sampling from most human organs is not possible. As a result, we have limited ability to study human molecular rhythms and relate them to either normal or disease physiology.One approach is to analyze temporally ...

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“…In addition to the specific ADAMs discussed above, limited evidence suggests that ADAM9, 97,98 ADAM12, 99,100…”

Section: Other Adams Implicated Cancermentioning

confidence: 99%

The ADAMs family of proteases as targets for the treatment of cancer

Mullooly

McGowan

Crown

et al. 2016

Cancer Biology & Therapy

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The ADAMs (a disintegrin and metalloproteases) are transmembrane multidomain proteins implicated in multiple biological processes including proteolysis, cell adhesion, cell fusion, cell proliferation and cell migration. Of these varied activities, the best studied is their role in proteolysis. However, of the 22 ADAMs believed to be functional in humans, only approximately a half possess matrix metalloproteinase (MMP)-like protease activity. In contrast to MMPs which are mostly implicated in the degradation of extracellular matrix proteins, the main ADAM substrates are the ectodomains of type I and type II transmembrane proteins. These include growth factor/cytokine precursors, growth factor/cytokine receptors and adhesion proteins. Recently, several different ADAMs, especially ADAM17, have been shown to play a role in the development and progression of multiple cancer types. Consistent with this role in cancer, targeting ADAM17 with either low molecular weight inhibitors or monoclonal antibodies was shown to have anticancer activity in multiple preclinical systems. Although early phase clinical trials have shown no serious side effects with a dual ADAM10/17 low molecular weight inhibitor, the consequences of long-term treatment with these agents is unknown. Furthermore, efficacy in clinical trials remains to be shown.

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ADAM9 Promotes Lung Cancer Metastases to Brain by a Plasminogen Activator-Based Pathway

Cited by 70 publications

References 47 publications

Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell–derived ADAM9

Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell–derived ADAM9

CYCLOPS reveals human transcriptional rhythms in health and disease

The ADAMs family of proteases as targets for the treatment of cancer

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