Triple-negative breast cancer (TNBC) is one of the most aggressive and metastatic breast cancer subtypes lacking targeted therapy. Our recent work demonstrated that circulating tumor cell (CTC) clusters and polyclonal metastasis of TNBC are driven by aggregation of CD44+ cancer stem cells (CSC) and associated with an unfavorable prognosis, such as low overall survival. However, there is no existing therapeutic that can specifically block CTC or CSC cluster formation. Methods: Using patient-derived xenograft (PDX) models, we established an ex vivo tumor cell clustering assay for a pilot screening of blockade antibodies. After identifying EGFR as a target candidate, we modulated the gene expression and inhibited its kinase activity to determine its functional importance in tumor cell clustering and therapeutic inhibition of lung metastasis. We also examined the molecular regulation network of EGFR and a potential connection to CSC marker CD44 and microRNAs, which regulate CTC clustering. Results: We report here that EGFR inhibition successfully blocks circulating CSC (cCSC) clustering and lung metastasis of TNBC. EGFR enhances CD44-mediated tumor cell aggregation and CD44 stabilizes EGFR. Importantly, blocking EGFR by a novel anti-EGFR monoclonal antibody (clone LA1) effectively blocked cell aggregation in vitro and reduced lung metastasis in vivo. Furthermore, our data demonstrated that the tumor suppressor microRNA-30c serves as another negative regulator of cCSC clustering and lung metastasis by targeting CD44 as well as its downstream effector EGFR. Conclusion: Our studies identify a novel anti-EGFR therapeutic strategy to inhibit cCSC aggregation and therefore abolish cCSC cluster-mediated metastasis of TNBC.
|Number of pages||12|
|State||Published - 2021|
Bibliographical noteFunding Information:
We are thankful to Skye Wang who has created the cover page image for the manuscript. We acknowledge the Liu laboratory members for their technical help and appreciate the tremendous support by Northwestern University Core facilities, including but not limited to the CTC Core, the Center for Comparative Medicine, Flow Cytometry Core, Small Animal Imaging, Microscopy Imaging, NUSeq, Bioinformatics, Mouse Histology & Phenotyping Laboratory, and Pathology Core. We also thank Case Western Reserve University Cancer Center Small Animal Facilities for their support. This project has been partially supported by the Department of Defense grant W81XWH-16-1-0021 and W81XWH-20-1-0679 (H. Liu), the NIH grants R00CA160638 and R01CA245699 (H. Liu and E.K. Ramos); Susan G. Komen Foundation CCR18548501 (X. Liu); American Cancer Society ACS127951-RSG-15-025-01-CSM (H. Liu); Northwestern University start-up grant (H. Liu), and NIH Fellowships T32 CA009560 (E.K. Ramos), T32 CA080621-15 (R. Taftaf), and T32GM008061 (E.J. Schuster).
© 2021 Ivyspring International Publisher. All rights reserved.
- CTC cluster
- Cancer stem cells
- Circulating cancer stem cell
- Circulating tumor cells
ASJC Scopus subject areas
- Medicine (miscellaneous)
- Pharmacology, Toxicology and Pharmaceutics (miscellaneous)