October 2015

Helping Anxious Zebrafish Calm Down

MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish

 

CHBIOL_22_10.c1.indd

Chemistry & Biology (2015) Volume 22, Issue 10, p1335–1346

Lundegaard et al. identify therapeutic potential for anti-cancer MEK-inhibitors to treat anxiety-like cAMP-mediated behaviors in zebrafish. Targeting cAMP-MAPK cross-talk pathways broadens the range of therapeutic targets for mental health disorders. This work illustrates the importance of whole-animal phenotypic screening in anxiety drug discovery and repurposing.

Summary

Altered phosphodiesterase (PDE)-cyclic AMP (cAMP) activity is frequently associated with anxiety disorders, but current therapies act by reducing neuronal excitability rather than targeting PDE-cAMP-mediated signaling pathways. Here, we report the novel repositioning of anti-cancer MEK inhibitors as anxiolytics in a zebrafish model of anxiety-like behaviors. PDE inhibitors or activators of adenylate cyclase cause behaviors consistent with anxiety in larvae and adult zebrafish. Small-molecule screening identifies MEK inhibitors as potent suppressors of cAMP anxiety behaviors in both larvae and adult zebrafish, while causing no anxiolytic behavioral effects on their own. The mechanism underlying cAMP-induced anxiety is via crosstalk to activation of the RAS-MAPK signaling pathway. We propose that targeting crosstalk signaling pathways can be an effective strategy for mental health disorders, and advance the repositioning of MEK inhibitors as behavior stabilizers in the context of increased cAMP.

MEK-Inhibitors-Reverse-cAMP-Mediated-Anxity-in-Zebrafish_Illustration

 

Read full article here

Live imaging reveals how wound healing influences cancer

Live imaging reveals how wound healing influences cancer

Live imaging reveals how wound influences cancer

Embo.org (2015) 

Click here to read article on Embo.org 

Researchers in the United Kingdom and Denmark have studied the “see-through” larvae of zebrafish to reveal how wound healing leads to skin cancer. Live imaging shows neutrophils, the protective inflammatory cells of the body’s immune system, diverted from an induced wound to any nearby precancerous skin cells. The newly arrived neutrophils cause rapid division of these skin cells, which may cause them to progress to melanoma. The results are published in The EMBO Journal.

“Our results provide direct visual evidence of a physical link between wound-associated inflammation and the development of skin cancer,” says EMBO Member Paul Martin, Professor at Bristol University and the University of Cardiff. “White blood cells, in particular neutrophils, that typically serve as part of the body’s built-in immune system are usurped by nearby precancerous skin cells in a way that leads to the proliferation of tumour cells in our zebrafish model experimental system of human melanoma.”

Scientists have known for some time that inflammation is one of the ten hallmarks of cancer. Cancer has also been described as a “wound that does not heal.” However details about how physical damage to body tissues might influence the progress of cancer have remained scarce.

The researchers used genetically modified larvae of zebrafish to watch the relationship between wound-associated inflammation and melanoma as the cancer took hold in the living fish. The cellular events and changes were observed by live imaging with a special confocal laser-scanning microscope.

In further experiments, the researchers were also able to show that a specific type of signaling molecule released by neutrophils, prostaglandin E2, is part of the signal that drives the splurge of cell growth linked to the cancer in their experimental system. High levels of neutrophils were also detected in human clinical samples of melanomas that had been obtained from individuals whose cancers had open ulcers. Importantly, neutrophils were linked to increased proliferation of melanoma cells and poor survival, which suggests that these findings in fish may have considerable relevance to cancer patients.

The authors note that the findings of the study may have implications for cancer surgery. Minimally invasive surgery is beneficial to cancer patients in many situations and often the preferred treatment. However, particularly in cases where all cancerous tissue cannot be removed, the inflammatory response might influence the remaining cancer cells in the body. “Our studies to date suggest that several strategies might improve outcomes for patients including the possible use of therapeutics to dampen damage-induced inflammatory responses,” adds Martin.

Further work is in progress to better understand the relationship between the inflammatory response and skin cancer in the zebrafish model system. Studies are also needed to investigate what therapeutic or other strategies might bring better interventions for patients who have adverse tissue inflammation due to planned (for example biopsy or surgery) or unplanned (e.g. ulceration) tissue damage.

Full research paper can be found in The Embo Journal. Click here to read the full paper

The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer”

Nicole Antonio, Marie Louise Bønnelykke-Behrndtz, Laura Ward, John Collin, Ib Jarle Christensen, Torben Steiniche, Henrik Schmidt, Yi Feng, Paul Martin

DMM Travel Grants

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DMM Travel Grants Available

Are you an early career scientist who is interested in attending a meeting or course relevant to the journal Disease Models & Mechanisms during 2015?

The Company of Biologists Grants Committee has allocated DMM with £10,000 to provide travel funds to conferences or courses for individuals working in the field of DMM. DMM applications are currently limited to travel that will be completed by the end of 2015.

Please visit the DMM website for further details on how to apply: DMM Travel Grants