Targeting ROR2 homooligomerization disrupts ROR2-dependent signaling and suppresses stem-like cell properties of human breast adenocarcinoma

Feng Leng; Jiajia Huang; Liufeng Wu; Jianchao Zhang; Xinxin Lin; Ruhuan Deng; Jinhang Zhu; Zhen Li; Zhenghao Li; Yimeng Wang; Han Zhang; Desheng Lu; Thomas J Kipps; Suping Zhang

doi:10.1016/j.isci.2024.111589

Targeting ROR2 homooligomerization disrupts ROR2-dependent signaling and suppresses stem-like cell properties of human breast adenocarcinoma

iScience. 2024 Dec 13;28(1):111589. doi: 10.1016/j.isci.2024.111589. eCollection 2025 Jan 17.

Authors

Feng Leng¹, Jiajia Huang², Liufeng Wu¹, Jianchao Zhang¹, Xinxin Lin¹, Ruhuan Deng¹, Jinhang Zhu¹, Zhen Li¹, Zhenghao Li¹, Yimeng Wang¹, Han Zhang³, Desheng Lu¹, Thomas J Kipps⁴, Suping Zhang^{1

4}

Affiliations

¹ Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Pharmacology, School of Basic Medical Sciences, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
² State Key Laboratory of Oncology in South China, Department of Medical Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
³ Xenta Biomedical Science Co., Ltd, Guangzhou 510060, China.
⁴ Moores Cancer Center, University of California, San Diego, San Diego, CA 92037, USA.

Abstract

Breast cancer stem-like cells (CSCs) are enriched following treatment with chemotherapy, and posited as having a high level of plasticity and enhanced tumor-initiation capacity, which can enable cancer relapse. Here, we show that such features are shared by breast cancer (BCA) cells that express receptor tyrosine kinase-like orphan receptor (ROR2), which is expressed primarily during embryogenesis and by various cancers. We find that Wnt5a can induce ROR2 homooligomerization to activate noncanonical Wnt signaling and enhance tumor-initiation capacity of BCA cells. Molecular analysis reveals that the cysteine-rich domain and transmembrane domain are required for ROR2 homooligomerization to activate ROR2. Treatment with a newly generated monoclonal antibody (mAb) specific for ROR2 can block Wnt5a-induced ROR2 homooligomerization, ROR2-dependent noncanonical Wnt signaling, and impair the capacity of BCA patient-derived xenografts to initiate tumor in immune-deficient mice. Collectively, these results indicate that targeting ROR2 (e.g., using mAb) suppresses BCA stemness and, thereby, may prevent BCA relapse.

Keywords: Cancer; Molecular interaction; Stem cell plasticity.