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Body-on-a-Chip Device Predicts Cancer Drug Responses

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Body-on-a-Chip
Credit: McAleer et al., Science Translational Medicine, 2019

Researchers continue to produce impressive miniature human tissues that resemble the structure of a range of human organs, including the livers, kidneys, hearts, and even the brain. In fact, some researchers are now building on this success to take the next big technological step: placing key components of several miniature organs on a chip at once.

These body-on-a-chip (BOC) devices place each tissue type in its own pea-sized chamber and connect them via fluid-filled microchannels into living, integrated biological systems on a laboratory plate. In the photo above, the BOC chip is filled with green fluid to make it easier to see the various chambers. For example, this easy-to-reconfigure system can make it possible to culture liver cells (chamber 1) along with two cancer cell lines (chambers 3, 5) and cardiac function chips (chambers 2, 4).

Researchers circulate blood-mimicking fluid through the chip, along with chemotherapy drugs. This allows them to test the agents’ potential to fight human cancer cells, while simultaneously gathering evidence for potential adverse effects on tissues placed in the other chambers.

This BOC comes from a team of NIH-supported researchers, including James Hickman and Christopher McAleer, Hesperos Inc., Orlando, FL. The two were challenged by their Swiss colleagues at Roche Pharmaceuticals to create a leukemia-on-a-chip model. The challenge was to see whether it was possible to reproduce on the chip the known effects and toxicities of diclofenac and imatinib in people.

As published in Science Translational Medicine, they more than met the challenge. The researchers showed as expected that imatinib did not harm liver cells [1]. But, when treated with diclofenac, liver cells on the chip were reduced in number by about 30 percent, an observation consistent with the drug’s known liver toxicity profile.

As a second and more challenging test, the researchers reconfigured the BOC by placing a multi-drug resistant vulva cancer cell line in one chamber and, in another, a breast cancer cell line that responded to drug treatment. To explore side effects, the system also incorporated a chamber with human liver cells and two others containing beating human heart cells, along with devices to measure the cells’ electrical and mechanical activity separately.

These studies showed that tamoxifen, commonly used to treat breast cancer, indeed killed a significant number of the breast cancer cells on the BOC. But, it only did so after liver cells on the chip processed the tamoxifen to produce its more active metabolite!

Meanwhile, tamoxifen alone didn’t affect the drug-resistant vulva cancer cells on the chip, whether or not liver cells were present. This type of cancer cell has previously been shown to pump the drug out through a specific channel. Studies on the chip showed that this form of drug resistance could be overcome by adding a second drug called verapamil, which blocks the channel.

Both tamoxifen alone and the combination treatment showed some off-target effects on heart cells. While the heart cells survived the treatment, they contracted more slowly and with less force. The encouraging news was that the heart cells bounced back from the tamoxifen-only treatment within three days. But when the drug-drug combination was tested, the cardiac cells did not recover their function during the same time period.

What makes advances like this especially important is that only 1 in 10 drug candidates entering human clinical trials ultimately receives approval from the Food and Drug Administration (FDA) [2]. Often, drug candidates fail because they prove toxic to the human brain, liver, kidneys, or other organs in ways that preclinical studies in animals didn’t predict.

As BOCs are put to work in testing new drug candidates and especially treatment combinations, the hope is that we can do a better job of predicting early on which chemical compounds will prove safe and effective in humans. For those drug candidates that are ultimately doomed, “failing early” is key to reducing drug development costs. By culturing an individual patient’s cells in the chambers, BOCs also may be used to help doctors select the best treatment option for that particular patient. The ultimate goal is to accelerate the translation of basic discoveries into clinical breakthroughs. For more information about tissue chips, take a look at NIH’s Tissue Chip for Drug Screening program.

References:

[1] Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. McAleer CW, Long CJ, Elbrecht D, Sasserath T, Bridges LR, Rumsey JW, Martin C, Schnepper M, Wang Y, Schuler F, Roth AB, Funk C, Shuler ML, Hickman JJ. Sci Transl Med. 2019 Jun 19;11(497).

[2] Clinical development success rates for investigational drugs. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Nat Biotechnol. 2014 Jan;32(1):40-51.

Links:

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

James Hickman (Hesperos, Inc., Orlando, FL)

Hesperos, Inc.

NIH Support: National Center for Advancing Translational Sciences


Using MicroRNA to Starve a Tumor?

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Endothelial cells are inhibited from sprouting
Credit: Dudley Lab, University of Virginia School of Medicine, Charlottesville

Tumor cells thrive by exploiting the willingness of normal cells in their neighborhood to act as accomplices. One of their sneakier stunts involves tricking the body into helping them form new blood vessels. This growth-enabling process of sprouting new blood vessels, called tumor angiogenesis, remains a vital area of cancer research and continues to yield important clues into how to beat this deadly disease.

The two-panel image above shows one such promising lead from recent lab studies with endothelial cells, specialized cells that line the inside of all blood vessels. In tumors, endothelial cells are induced to issue non-stop SOS signals that falsely alert the body to dispatch needed materials to rescue these cells. The endothelial cells then use the help to replicate and sprout new blood vessels.

The left panel demonstrates the basics of this growth process under normal conditions. Endothelial cells (red and blue) were cultured under special conditions that help them grow in the lab. When given the right cues, those cells sprout spiky extensions to form new vessels.

But in the right panel, the cells can’t sprout. The reason is because the cells are bathed in a molecule called miR-30c, which isn’t visible in the photo. These specialized microRNA molecules—and humans make a few thousand different versions of them—control protein production by binding to and disabling longer RNA templates, called messenger RNA.

This new anti-angiogenic lead, published in the Journal of Clinical Investigation, comes from a research team led by Andrew Dudley, University of Virginia Medical School, Charlottesville [1]. The team made its discovery while studying a protein called TGF-beta that tumors like to exploit to fuel their growth.

Their studies in mice showed that loss of TGF-beta signals in endothelial cells blocked the growth of new blood vessels and thus tumors. Further study showed that those effects were due in part to elevated levels of miR-30c. The two interact in endothelial cells as part of a previously unrecognized signaling pathway that coordinates the growth of new blood vessels in tumors.

Dudley’s team went on to show that levels of miR-30c vary widely amongst endothelial cells, even when those cells come from the very same tumor. Cells rich in miR-30c struggled to sprout new vessels, while those with less of this microRNA grew new vessels with ease.

Intriguingly, they found that levels of this microRNA also predicted the outcomes for patients with breast cancer. Those whose cancers had high levels of the vessel-stunting miR-30c fared better than those with lower miR-30c levels. While more research is needed, it does offer a potentially promising new lead in the fight against cancer.

Reference:

[1] Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β-induced Serpine1. McCann JV, Xiao L, Kim DJ, Khan OF, Kowalski PS, Anderson DG, Pecot CV, Azam SH, Parker JS, Tsai YS, Wolberg AS, Turner SD, Tatsumi K, Mackman N, Dudley AC. J Clin Invest. 2019 Mar 11;130:1654-1670.

Links:

Angiogenesis Inhibitors (National Cancer Institute/NIH)

Dudley Lab (University of Virginia School of Medicine, Charlottesville)

NIH Support: National Cancer Institute; National Heart, Lung, and Blood Institute


Putting Bone Metastasis in the Spotlight

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When cancers spread, or metastasize, from one part of the body to another, bone is a frequent and potentially devastating destination. Now, as you can see in this video, an NIH-funded research team has developed a new system that hopefully will provide us with a better understanding of what goes on when cancer cells invade bone.

In this 3D cross-section, you see the nuclei (green) and cytoplasm (red) of human prostate cancer cells growing inside a bioengineered construct of mouse bone (blue-green) that’s been placed in a mouse. The new system features an imaging window positioned next to the new bone, which enabled the researchers to produce the first series of direct, real-time micrographs of cancer cells eroding the interior of bone.


3D Action Film Stars Cancer Cell as the Villain

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For centuries, microscopes have brought to light the otherwise invisible world of the cell. But microscopes don’t typically visualize the dynamic world of the cell within a living system.

For various technical reasons, researchers have typically had to displace cells, fix them in position, mount them onto slides, and look through a microscope’s viewfinder to see the cells. It can be a little like trying to study life in the ocean by observing a fish cooped up in an 8-gallon tank.

Now, a team partially funded by NIH has developed a new hybrid imaging technology to produce amazing, live-action 3D movies of living cells in their more natural state. In this video, you’re looking at a human breast cancer cell (green) making its way through a blood vessel (purple) of a young zebrafish.

At first, the cancer cell rolls along rather freely. As the cell adheres more tightly to the blood vessel wall, that rolling motion slows to a crawl. Ultimately, the cancer cell finds a place to begin making its way across and through the blood vessel wall, where it can invade other tissues.


A Scientist Whose Music Gives Comfort

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Over the past few years, my blog has highlighted a wide range of Creative Minds from across biomedical research. But creative minds come in many forms, and, for a change of pace, I’d like to kick back this August and highlight some talented scientists who are also doing amazing things in the arts, from abstract painting to salsa dancing to rock’n’roll.

My first post introduces you to Dr. Pardis Sabeti, a computational geneticist at the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, and one of Time Magazine’s 2014 People of the Year for her work to contain the last major Ebola outbreak in West Africa. When she’s not in the lab studying viruses, Sabeti is the hard-driving voice of the indie rock band Thousand Days that has been rocking Boston for more than a decade.


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