Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis

Qiaozhu Zuo; Yongkang Yang; Yajing Lyu; Chen Yang; Chelsey Chen; Shaima Salman; Tina Yi-Ting Huang; Elizabeth E Wicks; Walter Jackson 3rd; Emmanuel Datan; Wenxin Qin; Gregg L Semenza

doi:10.1016/j.celrep.2023.112164

Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis

Cell Rep. 2023 Mar 28;42(3):112164. doi: 10.1016/j.celrep.2023.112164. Epub 2023 Feb 28.

Authors

Affiliations

¹ Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
² Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21205, USA.
³ Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
⁵ Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21205, USA; Departments of Biological Chemistry, Medicine, Pediatrics, and Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: gsemenza@jhmi.edu.

PMID: 36857181
DOI: 10.1016/j.celrep.2023.112164

Abstract

Intratumoral hypoxia is a microenvironmental feature that promotes breast cancer progression and is associated with cancer mortality. Plexin B3 (PLXNB3) is highly expressed in estrogen receptor-negative breast cancer, but the underlying mechanisms and consequences have not been thoroughly investigated. Here, we report that PLXNB3 expression is increased in response to hypoxia and that PLXNB3 is a direct target gene of hypoxia-inducible factor 1 (HIF-1) in human breast cancer cells. PLXNB3 expression is correlated with HIF-1α immunohistochemistry, breast cancer grade and stage, and patient mortality. Mechanistically, PLXNB3 is required for hypoxia-induced MET/SRC/focal adhesion kinase (FAK) and MET/SRC/STAT3/NANOG signaling as well as hypoxia-induced breast cancer cell migration, invasion, and cancer stem cell specification. PLXNB3 knockdown impairs tumor formation and lung metastasis in orthotopic breast cancer mouse models.

Keywords: CP: Cancer; HIF-1; MET; Plexin-B3; cancer stem cells; focal adhesion kinase; hypoxia; invasion; metastasis; migration; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms* / pathology
Cell Hypoxia / genetics
Cell Line, Tumor
Cell Movement
Female
Gene Expression Regulation, Neoplastic
Humans
Hypoxia / metabolism
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Lung Neoplasms* / pathology
Mice
Neoplastic Stem Cells / metabolism

Substances

Hypoxia-Inducible Factor 1, alpha Subunit
plexin
MET protein, human
PLXNB3 protein, human