The researchers genetically engineered a strain of mice to make either Myc or another cancer-associated protein called Ras in the proximal tubules of the kidney when a compound called doxycycline, which had been added to their drinking water, was removed from it. (Myc and Ras are not normally produced at high levels by these cells.) Ras-producing mice did not get cancer. But within just a few weeks, the mice that made Myc developed kidney cancers that mimicked an aggressive subset of human renal cell adenocarcinoma that originates in the kidney’s collecting ducts. Adding doxycycline back to the animals’ water caused the tumors to shrink dramatically.
The researchers then turned to a new tissue analysis technique called desorption electrospray ionization mass-spectrometric imaging, or DESI-MSI, recently developed by postdoctoral scholar Livia Eberlin, PhD, in the Zare laboratory to compare cancerous and normal tissue.
DESI-MSI creates a highly detailed, two-dimensional map of the chemical composition of a tissue sample through a process that can be loosely compared to a specialized car wash. Samples are sprayed with a thin, high-powered stream of liquid droplets that dissolve their outer surface. The resulting back spray, which contains molecules from the surface of the sample, is collected and analyzed by mass spectrometry. By moving the sample around in a two-dimensional plane, it’s possible to make a chemical map of the tissue.
Distinct chemical composition
The researchers found that the cancerous kidney tissue had a chemical composition distinct from that of healthy tissue. In particular, it had higher-than-normal levels of molecules generated as glutamine is metabolized. Blocking the activity of a protein called glutaminase, which is responsible for metabolizing glutamine, caused the animals’ tumors to grow more slowly when doxycycline was removed from their drinking water.
Finally, the researchers showed that both Myc and glutaminase levels are also high in human samples of renal cell adenocarcinoma tumors, indicating that it may be useful to test whether blocking the glutamine pathway is a viable treatment for patients with the disease.
Using this new technique, we may now be able to sort many kidney cancers into discrete types.
The researchers are now planning to create additional mouse models of other types of kidney cancer. “Using this new technique, we may now be able to sort many kidney cancers into discrete types. We’re also planning on using DESI-MSI to find new therapies for kidney but also liver cancers and lymphomas,” Felsher said
Felsher emphasized that the study was only possible with the concerted effort of chemists in the Zare laboratory. “This was a true cross-disciplinary effort,” Felsher said. “I am proud and excited about the outcome of this collaboration.”
Other Stanford authors are postdoctoral scholars Livia Eberlin, PhD, Arvin Gouw, PhD, Meital Gabay, PhD, and Stephanie Casey, PhD; former postdoctoral scholars Stacey Adam, PhD, and David Bellovin, PhD; and instructor Yulin Li, MD, PhD.
The research was supported by the Burroughs Welcome Fund, the Damon Runyon Foundation, the National Institutes of Health, the Leukemia and Lymphoma Society, the American Lung Association and L’Oreal for Women in Science.
Stanford’s Department of Medicine also supported the work.