Northwestern Medicine investigators have discovered novel features of circulating tumor stem cells can promote chemotherapy evasion and metastasis in triple-negative breast cancer (TNBC), according to a recent study published in the journal Cancer Discovery.
The findings suggest a new therapeutic target to prevent therapy evasion and new dissemination in metastatic breast cancer and improving patient outcomes, according to Huiping Liu, MD, PhD, associate Professor of Pharmacology, of Medicine in the Division of Hematology and Oncology, and senior author of the study.
“Cancer metastasis accounts for 90 percent of deaths related to breast cancer and other solid tumors. Identifying therapeutic targets and approaches to prevent and treat metastasis will pave the road for the development of life-saving solutions,” said Liu, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Cancer metastasis in solid tumors, including breast cancer, is caused by circulating tumor cells (CTCs) shedding from the primary tumor, infiltrating the bloodstream and disseminating into distant organs for tumor regeneration, a process known as “metastatic seeding.” The risk of metastasis is 20- to 100-fold higher when these cells become multicellular CTC clusters with stem cell properties.
Previous work from the Liu Laboratory has established that CTC clusters drive metastasis in aggressive breast cancer, including TNBC. However, the specific intracellular changes that enable CTC clusters to escape therapies, such as chemotherapy, in TNBC have remained poorly understood, according to Liu.
“Breast cancer stem cells such as circulating tumor stem cells are capable of modifying their inner plasticity programs and outside face profiles in many dynamic ways to adapt to stressful conditions such as therapies and metastasis. Knowing all the tricks and patterns of circulating tumor stem cells play will help us find best strategies to counter against their evasion and spreading, corner these devastating cancer cells with new therapeutics, and thereby saving patient lives,” Liu said.
In the current study, Liu’s team studied CTC clusters in TNBC cell lines both treated and not treated with paclitaxel chemotherapy, finding that the loss of the ST6GAL1 protein — or deficiency in certain sugar residues and sialic acids of the surface proteins — increases TNBC stem cells’ ability to evade chemotherapy and metastasize.
The team then investigated the efficacy of therapeutically targeting PODXL using a neutralizing antibody in TNBC tumor models and found that this anti-PODXL antibody blocked CTC cluster formation and subsequent metastasis to vital organs.
Overall, the findings suggest that PODXL could be used as a therapeutic target to counteract chemotherapy evasion and metastasis in TNBC. According to Liu, next steps include using artificial intelligence, such as machine learning and deep learning approaches, to enhance TNBC drug development.
“The goal is to not only target cancer stem cells and circulating tumor cell clusters, but also strengthen the immune defense mechanisms which help outsmart and checkmate the vicious cancer cells from spreading and regenerating new tumors in local and distant places,” Liu said.
Nurmaa Dashzeveg, PhD, research assistant professor of Pharmacology, was lead author of the study. Co-authors include Yuzhi Jia, MD, PhD, research assistant professor of Pharmacology,
Youbin Zhang, PhD; research assistant professor of Medicine in the Division of Hematology and Oncology; Emma Schuster, a student in the Driskill Graduate Program in Life Sciences (DGP); David Scholten, a DGP student; Lamiaa El-Shennawy, PhD, research assistant professor of Pharmacology; Qiang Zhang, PhD, research professor of Medicine in the Division of Hematology and Oncology; Leonidas Platanias, MD, PhD, the Jesse, Sara, Andrew, Abigail, Benjamin and Elizabeth Lurie Professor of Oncology and director of the Lurie Cancer Center; Ami Shah, ‘11 MD, ‘14 GME, assistant professor of Medicine in the Division of Hematology and Oncology; William Gradishar, MD, the Betsy Bramsen Professorship of Breast Oncology and chief of Hematology and Oncology in the Department of Medicine; and William Muller, MD, PhD, the Janardan K. Reddy, MD Professor of Pathology.
Shah, Gradishar and Muller are also members of the Lurie Cancer Center.
This work was supported by the Department of Defense grants BC150596 and BC190982; National Institute of Health grants R01CA245699, R01 GM115234, S10OD018530 and R24GM137782; American Cancer Society grants ACS127951-RSG-15-025-01-CSM; Komen Foundation grant CCR15332826, the H Foundation, the Lynn Sage Breast Cancer Foundation and a Northwestern University start-up grant.
