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Researcher Profile: Dr. Stephen Schmechel

Nerve Tissue Tumors and Signaling Pathways

No hesitation for Dr. Stephen Schmechel—he dives right in: “We use specimens in lots of ways.”

One particular way on his mind is the research behind a paper recently accepted in the journal Cancer Discovery. The paper describes how Schmechel and his colleagues have found one of the gene-controlled pathways leading to increased malignant peripheral nerve sheet tumors. The pathway presents targets for new treatments, which is important because these tumors are highly lethal and have not responded well to treatment in the past.

Now that some of the genetic “switches” behind development of these tumors are known, the pathway to tumor development can be blocked by inhibiting the activity of certain genes.

Schmechel and his colleagues first explored the pathway, called the Wnt/β-catenin signaling pathway, in mice. The signaling pathway was a promising avenue for research since it crops up in other types of cancer, but it had not been explored yet in peripheral nerve sheet tumors.

They created a mouse model whose Wnt/β-catenin signaling pathway could be manipulated in experiments by selectively inserting certain DNA elements called transposans and its associated enzyme, transposase. Transposase clips out the transposon, replicates it, and scatters it randomly throughout its host’s genome, leading to a tremendous increase in mutations.

This research would not be possible in humans, but is an important approach for testing drug treatment success in mice with similarly accelerated mutations that eventually lead to cancer.

Once these mutations were observed, Schmechel could detect a link between malignant tumor development and cells containing higher levels of β-catenin in their cores. The research team could also see more precisely which mutations became cancerous and which were merely “ride-along” accidents that occur during the general chaos of increased mutation rates. (Most mutations are not cancerous, and many are repaired by intrinsic cellular mechanisms.)

The researchers next turned to considering the Wnt/β-catenin signaling pathway in human Schwann cells, the cells where malignant peripheral nerve sheath tumors appear to begin growing.

Many cellular mechanisms likely trigger the Wnt pathway, promoting tumor growth in Schwann cells. The human tissue experiments helped prove that β-catenin is particularly associated with the development of malignant peripheral nerve sheath tumors (as opposed to other sorts of nerve-tissue tumors.)

The team next tried to pin down exactly which genes activated and/or suppressed β-catenin expression. Once the line-up of gene “perpetrators” was identified, the team systematically “knocked out” one gene after the other to observe which genes’ expression promoted or inhibited tumor growth.

They went even further, testing two compounds they thought could block the Wnt/β-catenin signaling pathway. Normal cells resisted the targeted compounds, but the cell lines associated with higher β-catenin levels (and, thus, higher tumor levels) were sensitive to the compounds.

The end result was the demonstration of likely cellular targets these compounds could hit, interrupting the Wnt/β-catenin signaling pathway and halting the development of the highly malignant nerve tumors.

The set of experiments neatly illustrated how science can identify a problem (a lethal, hard-to-treat form of cancer), replicate and manipulate the problem (in mouse models), and then solve the problem in human tissue cells, giving drug developers new, more precise targets for blocking cell proliferation, while giving clinicians a clearer way to try curing their patients.

“It’s a very nice illustration of how translational science uses human biospecimens,” Schmechel says. And, while he is aware that some people are leery of collaborations between researchers and drug development companies, he reminds people that clinical trials in academic settings are useless until they succeed in an FDA-approved drug or device or service that can hit the marketplace and be put to clinical use. Getting this kind of marketplace readiness takes the data-crunching, clinical trial ability, technical expertise, and funding offered by drug development companies.

“We end up working with a lot of companies,” Schmechel says. “If we don’t, all discoveries just sit in the university.”

 

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Dr. Stephen Schmechel