Northwestern Medicine scientists have discovered how circulating tumor cells in the blood cluster together during metastasis — findings that reveal a novel mechanism for how cancer spreads and a potential new target for treatment.
“Ninety percent of people with solid tumors die from metastasis. Understanding how tumor cells spread will help us develop therapeutics to prevent and treat metastatic cancer — and therefore eventually reduce cancer mortality,” said Huiping Liu, MD, PhD, associate professor of Pharmacology and lead author of the study published in the journal Cancer Discovery.
Xia Liu, PhD, research assistant professor of Pharmacology, was the first author of the paper.
During metastasis, cells called circulating tumor cells (CTCs) shed from the original tumor and travel through the blood system, where they seed new cancer growth in other parts of the body. Previously, research from co-author Massimo Cristofanilli, MD, and others had shown that compared to single CTCs, clusters of CTCs detectable in patients’ blood are associated with particularly poor survival. However, the molecular mechanisms of tumor cell cluster formation — and how CTCs mediate cancer metastasis — remained unclear.
In the new study, the scientists first demonstrated in a model of breast cancer that CTC clusters are the result of individual tumor cells aggregating together in the blood (rather than collective shedding and migration).
They also identified the mechanism of cluster formation: Cancer cells with stem cell properties contain a surface protein called CD44 that help the cells bind together.
“Like the old saying ‘birds of a feather flock together,’ cancer stem cells of identical surface proteins aggregate as small clusters during travel,” Liu explained. “CD44 not only marks cancer stem cells, but also attracts two neighboring cells to bind together — thereby activating protein networks responsible for cellular aggregation and stem cell programing.”
The scientists further found that reducing CD44 and its downstream signaling partner PAK2 effectively prevented the aggregation of tumor cells.
The findings suggest that targeting the cancer-specific CD44 network— by depleting the gene or blocking protein interactions in cancer cells with specific antibodies, for example — could be a path toward preventing metastasis.
“There is an urgent need to therapeutically intervene in the cluster formation of circulating tumor cells,” Liu said. “Our studies shed light on the mechanistic understanding and strategic targeting of these clusters in the search for a cure for cancer.”
Liu is also an associate professor of Medicine in the Division of Hematology and Oncology and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Other Northwestern authors of the paper include Massimo Cristofanilli, MD, professor of Medicine in the Division of Hematology and Oncology and associate director for Translational Research at the Lurie Cancer Center; Rokana Taftaf, MD, a graduate student in the Driskill Graduate Program in Life Sciences (DGP), and Elizabeth Tsui, a student in the Medical Scientist Training Program (MSTP); and Madoka Kawaguchi, Wenjing Chen, Youbin Zhang, Lorenzo Gerratana, MD, Dhwani Patel and Valery Adorno-Cruz.
The study was also co-authored by scientists from Albert Einstein College of Medicine and Case Western Reserve University, among other institutions.
The study was supported, in part, by National Institutes of Health (NIH)/National Cancer Institute (NCI) grants R00CA160638, CA150344, CA100324 and CA216248; NIH/National Institute of General Medical Sciences grant R35GM124952; American Cancer Society grant ACS127951-RSG-15-025-01-CSM; the Susan G. Komen Foundation CCR15332826; the Department of Defense W81XWH-16-1-0021; Ohio Cancer Research Associates; Case Comprehensive Cancer Center (NCI P30 CA043703 Pilot Grant); Case Western Reserve University and Northwestern University start-up grants; the Albert Einstein College of Medicine Gruss Lipper Biophotonics Center and its Integrated Imaging Program; the Lynn Sage Cancer Research Foundation and Case Western Reserve University CTSA/ KL2 TR0002547.