“Why doesn’t cancer metastasize to your muscles?”

From the Ghajar Lab, Breast & Ovary Cancer Program, Cancer Consortium

As tumors grow, individual cancer cells can break off and circulate in the bloodstream. Like tiny seeds, these disseminating tumor cells (DTCs) often lodge in other organs and exploit the fertile, healthy tissue to form new growths. This process, called metastasis, can be catastrophic for patients as most cancer deaths result from metastases, not the primary tumors – but there’s one tissue that’s incredibly resistant: skeletal muscle. Skeletal muscle, the tissue that makes up your biceps or quadriceps, is different from the cardiac muscle in your heart or the smooth muscle in your intestines. And, it turns out, it’s different when it comes to metastasis too. “Why don’t we get skeletal muscle metastases?” asks Dr. Sarah Crist, a former PhD student in Dr. Cyrus Ghajar’s lab. Dr. Ghajar studies breast cancer metastasis, and specifically anti-metastatic niches, as an Associate Professor at Fred Hutch. “When Cyrus first posed this question to me and walked me through what was known (or really, unknown) about the biology underlying the anti-metastatic nature of skeletal muscle, I was hooked,” said Dr. Crist. “It’s such a simple yet captivating concept. Skeletal muscle makes up such a large percentage of a person’s body mass [30-40%] and yet despite this, metastases rarely arise in this tissue.” This mystery drove Dr. Crist to characterize the skeletal muscle niche in a new publication in Nature Cell Biology.

In this manuscript, Dr. Crist leads a detailed investigation into the metabolic state of DTCs in the skeletal muscle microenvironment. A critical component of her study involves redox, or reduction-oxidation: a chemical process that dynamically balances the metabolic generation of reactive oxygen species (ROS) against antioxidants. When this balance is shifted towards the creation of ROS, it leads to cellular stress and a highly oxidized state. Dr. Crist and her collaborators found that skeletal muscle, perhaps because of its high metabolic requirements and constant tear/repair cycles, exhibits such a redox imbalance. “Our manuscript adds to mounting evidence that sustained oxidative stress should be considered a hallmark of DTC biology and that this state might be exploited for metastasis prevention,” explained Dr. Crist. “Here we show that sustained oxidative stress drives a profound redox imbalance in disseminated tumor cells (DTCs) in skeletal muscle and DTCs are actually incapable of progressing past this single cell stage because of this.” Essentially, the DTCs can seed skeletal muscle as single cells. However, because of the stresses they experience once settled into the skeletal muscle microenvironment, those single cells very rarely proliferate to form tumors.

A graphic showing how breast cancer cells can break off from the main tumor and disseminate throughout the body, seeding metastases in many tissues. A new study by Crist et al shows why these disseminating tumor cells (DTCs) are incapable of seeding metastases in skeletal muscle tissue.
Cancer cells that break off from primary tumors in the breast are capable of lodging in and growing in other organs, such as the lungs. However, researchers Dr. Crist and Dr. Ghajar noticed that you don’t see such metastases in skeletal muscle. Along with a multi-disciplinary team of researchers, they showed that this is because of the sustained oxidative stress in muscle tissue, and the physiological stress it places on the cancer cells. Figure provided by Dr. Sarah Crist, PhD

When I asked Dr. Crist what new questions her findings brought up, she was very enthusiastic. “Oh boy, so many new questions! There’s so much food for thought. For example, big picture questions like: How do other anti-metastatic niches (e.g. spleen, thyroid) maintain control over DTCs? What is the metabolic landscape of DTCs across metastatic and anti-metastatic sites? And how does the microenvironment shape the metabolic behavior of single DTCs?” As is often the case in novel scientific studies, it seems like the answers obtained through this study sparked an equal number of new research avenues.

As is also often the case in novel scientific research, this project was profoundly collaborative. Thanks to the Cancer Consortium, “it has been so easy to collaborate with other researchers at the Hutch and UW, and this opened so many doors for us,” gushed Dr. Crist. “Without the help of others, we just wouldn’t be able to tell the story you read today.” Contributing to this work were Cancer Consortium members Dr. Peter Nelson, who provided expertise in human tissue processing and IHC staining, Dr. Larry True, a renowned pathologist, Dr. Lucas Sullivan, a “bonafide metabolism expert” according to Dr. Crist, and Dr. Stephen Tapscott, “an incredible sounding board …[who] provided constructive feedback every step of the way.”

With an eye towards the future, I asked Dr. Crist about how her findings might inform advances in treatment of DTCs for breast cancer patients. “We believe that if we can find a way to sustain high oxidative stress, we might be able to block this transition to growth for DTCs in metastatic sites,” she said. “If we can find a way to exceed a DTC’s threshold for stress, we might actually be able to outright kill this metastasis-initiating population. We [also] provide evidence that if our observed phenomenon could be perpetuated in lung, it would restrict metastasis there.”

Crist SB, Nemkov T, Dumpit RF, Dai J, Tapscott SJ, True LD, Swarbrick A, Sullivan LB, Nelson PS, Hansen KC, and Ghajar CM. 2022. Unchecked oxidative stress in skeletal muscle prevents outgrowth of disseminated tumour cells. Nature Cell Biology. 24: 538-553. doi: 10.1038/s41556-022-00881-4.

This work was funded by the W. M. Keck Foundation, start-up funds from the Fred Hutchinson Cancer Center, Training Grants from the NIH, the Comprehensive Cancer Center Support Grant, the Pacific Northwest Prostate SPORE grant, and the Department of Defense Breast Cancer Research Program.

Fred Hutch/UW Cancer Consortium members Dr. Cyrus Ghajar (Fred Hutch), Dr. Stephen Tapscott (Fred Hutch), Dr. Lawrence True (UW), Dr. Lucas Sullivan (Fred Hutch), and Dr. Peter Nelson (Fred Hutch) contributed to this work.