Identifying New Targets in Cancer Metabolism and Treatment

Progress in cancer research over the past ten years has helped scientists gain a greater understanding of cancer cell metabolism and how cancer cells interact – metabolically speaking – with neighboring cells in the tumor microenvironment in order to secure the nutrients they need to proliferate.

“Learning which conversations between cancer cells and their neighbors to interrupt could potentially point us to new targets for treatments that are more effective than those in use today,” said Deepak Nagrath, associate professor, who joined the BME faculty in January 2017.

In ongoing work begun at Rice University, Nagrath takes a systems biology approach, combining a metabolic isotope tracing technique with a computational framework, together known as 13C-based metabolic flux analysis. He has conducted a number of studies to more fully understand the metabolism of cancer cells as well as their interactions with their immediate environment.

In work published in November 2016 in Cell Metabolism, Nagrath focused on glutamine, an amino acid for which many types of cancer cells have been shown to have a voracious appetite. He also focused on the related enzyme glutamine synthetase in the stroma, or the connective tissue that makes up the tumor microenvironment.

In ovarian cancer cells, Nagrath’s team found greater expression of genes that control glutamine production than in normal cells and that, when the cancer cells were put into a glutamine-deprived environment, surrounding cells known as cancer-associated fibroblasts (CAFs) began producing higher than normal levels of the amino acid.

Upon further investigation, the researchers observed an interesting dynamic between the cancer and stromal cells: The cancer cells appeared to barter with their neighbors. The cancer cells contributed two enzymes, lactate and glutamate, and in exchange, the neighboring CAFs used the enzymes to produce – and share – glutamine.

But when the team inhibited glutamine production by the neighboring CAFs using drugs or through depriving them of nutrients, the ovarian cancer cells stopped growing.

Precisely how ovarian and other types of cancer cells metabolically coax their neighbors to produce nutrients is still not fully known, but Nagrath’s latest work helps snap another important puzzle piece in place.

“We now know that targeting glutamine-producing enzymes in the tumor microenvironment slowed the growth of tumors,” he said. “This suggests to us that using a combination of therapies, rather than just one, to simultaneously target glutamine production and metabolism within cancer cells as well as in their surrounding environment may help us improve treatment.”

The work was funded by a St. Louis Ovarian Cancer Research Awareness grant.

Yang, L. Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metabolism, 24 (2016), 685-700;

Turning blood into a laser emitter for drug testing, cancer treatment

University of Michigan researchers have successfully demonstrated a new technique that combines laser light with an FDA-approved fluorescent dye to monitor cell structure and activity at the molecular level. This could lead to improved clinical imaging and better monitoring of tumors and other cell structures. It could also be used during drug testing to monitor the changes that cells undergo when exposed to prospective new drugs.

The team, led by Biomedical Engineering professor Xudong (Sherman) Fan, shined laser light into a small laser cavity containing whole human blood infused with Indocyanine green, an FDA-approved fluorescent dye. By analyzing the light that was reflected back out, researchers observed cell structures and changes within the blood on the molecular level.

A key advantage of the new technique over current methods is the ability to process laser light—it can be amplified to make small changes easier to see or filtered to remove unwanted background noise. Current methods use similar dyes with infrared or visible light, relying on visible fluorescence to observe cell activity and making small changes can be difficult to see.

Currently, the researchers have only demonstrated the technique on whole blood outside the body. But they predict that in the future, they may be able to use it on tissue inside the body. This could enable better monitoring of cell activity and tissue properties inside the body, or enable a surgeon to precisely identify the edge of a tumor during guided surgery.

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Researchers use ovarian follicles to preserve fertility Technique could be beneficial for women with cancer; study in mice produced live births

From: U-M Comprehensive Cancer Center News
Media contact: Nicole Fawcett, 734-764-2220 |  Patients may contact Cancer AnswerLine™, 800-865-1125

ANN ARBOR, Mich. — Researchers at the University of Michigan have identified a potential new approach to fertility preservation for young cancer patients that addresses concerns about beginning cancer treatment immediately and the possibility of reintroducing cancer cells during the fertility preservation process.

The work, done in mice, has potential to expand options for girls and women undergoing cancer treatments that may impact their future fertility.

The researchers isolated primary ovarian follicles, consisting of the oocyte and surrounding cells. They encapsulated the follicles in a gel and then reimplanted them in mice. All mice transplanted with the follicles resumed normal ovarian cycles. One-third produced live births.

For many young women diagnosed with cancer, concerns about fertility rank high and may influence their decisions about cancer treatment. Current fertility preservation options for women include embryo or egg freezing, performed using hormonal stimulation to induce ovulation. Hormonal stimulation is not possible for all young patients. Some are too young and some cannot afford to delay cancer treatment.

Jacqueline Jeruss“This research is an important advance in the potential expansion of fertility preservation options for young patients who may not be able to undergo hormone stimulation to induce ovulation before beginning chemotherapy,” says study author Jacqueline S. Jeruss, M.D., Ph.D., associate professor of surgery and director of the Breast Care Center at the University of Michigan Comprehensive Cancer Center.

“This study also provides new information on a method to reduce or eliminate cancer cell exposure during the fertility preservation process,” she adds.

Fear of reintroducing cancer

Researchers are also studying ovarian tissue transplantation for patients with cancer. A key concern with this approach is the risk that the ovarian tissue may harbor latent cancer cells that, upon transplantation, could be reintroduced back into the patient. Cancer cells are known to circulate throughout the body even in early stage invasive disease.

In this new study, when researchers isolated the follicles, they substantially reduced the presence of cancer cells. Two of the five tested transplanted materials had no residual cancer cells.

Lonnie Shea“The success rate for traditional in vitro fertilization is approximately 33 percent per cycle. For cancer patients, the oocytes or embryos that are cryo-preserved before cancer treatment may become their entire reproductive future,” says study author Lonnie D. Shea, Ph.D., William and Valerie Hall Chair and professor of biomedical engineering at the University of Michigan.

“The ovary can have tens to hundreds of thousands of follicles. If we can access that pool to preserve fertility, we could potentially create many more chances for reproductive success for these patients,” Shea adds.

Refining the technique

The authors tested three types of biomaterial for preserving the follicles. They hope that by refining their study techniques they can produce even better results. Additional research is also needed to ensure that all cancer cells are consistently eliminated from the follicles every time this tissue is transplanted.

As the work’s promise continues, the researchers envision that ovarian follicles could be extracted and preserved till the woman was ready to pursue pregnancy. At that point, the follicles would be matured and then fertilized. More research is needed before this technique can be tested in humans.

“Fertility is an important part of survivorship for young cancer patients,” Jeruss says. “It’s crucial to identify new techniques to make more fertility preservation options available for women and girls being treated for cancer.”

The study is published in the Nature journal Scientific Reports.

Note to patients: This work was done in mice and is not currently available for use in humans. Call the Cancer AnswerLine at 800-865-1125 to speak to a nurse about available fertility preservation options.

Additional authors: Ekaterina Kniazeva and Teresa K. Woodruff, from Northwestern University; A.N. Hardy from Fox Chase Cancer Center; Samir Boukaidi, from Centre Hospitalier Universitaire de Nice

Funding: National Institutes of Health grant U54 HD076188

Disclosure: None

Reference: Scientific Reports, “Primordial Follicle Transplantation within Designer Biomaterial Grafts Produce Live Births in a Mouse Infertility Model,” published online Dec. 3, 2015,doi:10.1038/srep17709

Cancer decoy could capture malignant cells and warn of relapse A small, implantable device that researchers are calling a cancer “super-attractor” could eventually give doctors an early warning

A small, implantable device that researchers are calling a cancer “super-attractor” could eventually give doctors an early warning of relapse in breast cancer patients and even slow the disease’s spread to other organs in the body.

The sponge-like device developed at the University of Michigan is designed to attract the cancer cells that emerge in the bloodstream during the early stages of cancer’s recurrence—before tumors form elsewhere in the body. A new study in mice shows that the device attracts detectable numbers of cancer cells before they’re visible elsewhere in the body. It also shows that the cancer cells spread to the lungs 88 percent more slowly in the mice that received the implants. Cancer cells also spread more slowly to the liver and other organs. The team’s findings are reported in a new paper published in the journal Nature Communications.

Researchers envision the super-attractor being implanted just beneath the skin of breast cancer patients. Doctors could monitor it using a non-invasive scan and it could enable them to detect and treat relapse sooner. It also has the potential to be used as a preemptive measure in those who are at high risk for breast cancer.

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U-M Researchers construct cancer "super-attractor" scaffolds from mouse tissue, using a tumor as a control in the experimental process at the NCRC. Photo by: Joseph Xu

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U-M Researchers construct cancer "super-attractor" scaffolds from mouse tissue, using a tumor as a control in the experimental process at the NCRC. Photo by: Joseph Xu


“Breast cancer is a disease that can recur over a long period in a patient’s life, and a recurrence is often very difficult to detect until the cancer becomes established in another organ,” said Jacqueline Jeruss, an associate professor of surgery in the U-M Comprehensive Cancer Center and an author on the paper. “Something like this could be monitored for years and we could use it as an early indicator of recurrence.”

Jeruss said the idea for the super-attractor was born from the knowledge that cancer cells don’t spread randomly. Instead, they’re attracted to specific areas within the body. So the team worked to design a device that exploited that trait.

“We set out to create a sort of decoy—a device that’s more attractive to cancer cells than other parts of the patient’s body,” explained Lonnie Shea, the William and Valerie Hall Department Chair of Biomedical Engineering at U-M and an author on the paper. “It acts as a canary in the coal mine. And by attracting cancer cells, it steers those cells away from vital organs.”

The device takes advantage of interaction that naturally takes place between cancer and the body’s immune system. Cancer co-opts the immune system, turning a patient’s immune cells into drones that gather in specific organs to prepare them for the arrival of cancer cells. The immune cells then act like a beacon in the body that attracts cancer to that location. In essence, the team has built a brighter beacon.

When the super-attractor was implanted just beneath the skin of the mice in the study, their cancer-compromised immune systems responded as they would to any foreign object, sending out cells to attack the intruder. Cancer cells were then attracted to the immune cells within the device, where they took root in tiny pores designed to be hospitable to them. The study also found that the cells captured by the implant didn’t group together into a secondary tumor, as they normally would.

Grace Bushnell, BME PhD Student, and Shreyas Rao, BME Research Fellow, look at efficacy results of the cancer "super-attractor." Photo by: Joseph Xu

Grace Bushnell, BME PhD Student, and Shreyas Rao, BME Research Fellow, look at efficacy results of the cancer "super-attractor." Photo by: Joseph Xu

Grace Bushnell, BME PhD Student, and Shreyas Rao, BME Research Fellow, look at efficacy results of the cancer "super-attractor." Photo by: Joseph Xu

Grace Bushnell, BME PhD Student, and Shreyas Rao, BME Research Fellow, look at efficacy results of the cancer "super-attractor." Photo by: Joseph Xu


“We were frankly surprised to see that cancer cells appeared to stop growing when they reached the implant,” Shea said. “We saw individual cells in the implant, not a mass of cells as you would see in a tumor, and we didn’t see any evidence of damage to surrounding tissue.

The team is evaluating non-invasive scanning technologies that could be used to monitor the device. They’re looking at ultrasound as well as a light-based technology called optical coherence tomography. Such a technology could enable doctors to detect cancer cells in the implant simply by holding a probe to a patient’s skin.

The device’s spongy structure is particularly attractive to circulating cancer cells. It’s made of an FDA-approved material that’s already widely used in surgical sutures and harmlessly dissolves in the body over time. The device implanted in the mouse study was only a few millimeters in diameter; a human-sized version might be a bit larger than a pencil eraser.

While it’s likely several years away from being used on patients, Shea believes the technology could potentially be used for other types of cancer as well, including pancreatic and prostate cancer. The device could also be an important tool in the emerging field of precision medicine, where cells captured in the device could be analyzed to identify the best therapies for individual patients. The team is now working to gain a better understanding of why cancer cells are attracted to specific areas of the body and why they’re so strongly attracted to the device. Shea believes that this information could lead to new insight into how cancer metastasizes and how to stop it.

Shreyas Rao, BME Research Fellow, shows the cancer "super-attractor" in the NCRC. Photo by: Joseph Xu

Shreyas Rao, BME Research Fellow, shows the cancer "super-attractor" in the NCRC. Photo by: Joseph Xu

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Shreyas Rao, BME Research Fellow, shows the cancer "super-attractor" in the NCRC. Photo by: Joseph Xu


“A detailed understanding of why cancer cells are attracted to certain areas in the body opens up all sorts of therapeutic and diagnostic possibilities,” he said. “Maybe there’s something we can do to interrupt that attraction and prevent cancer from colonizing an organ in the first place.”

The paper is titled “In vivo capture and label-free detection of early metastatic cells.” Funding was provided by the National Institutes of Health (grant number R01CA173745) and the Northwestern H Foundation Cancer Research Award. The university is pursuing patent protection for the intellectual property and is seeking commercialization partners to help bring the technology to market.