Noncanonical Wnt/Ror2 signaling regulates cell–matrix adhesion to prompt directional tumor cell invasion in breast cancer

Abstract

Cell-extracellular matrix (ECM) interactions represent fundamental exchanges during tumor progression, yet how particular signal-transduction factors prompt the conversion of tumor cells into migratory populations capable of systemic spread during metastasis remains elusive. We demonstrate that the noncanonical Wnt receptor, Ror2, regulates tumor cell-driven matrix remodeling and invasion in breast cancer. Ror2 loss-of-function triggers the disruption of E-cadherin within tumor cells, accompanied by an increase in tumor cell invasion and collagen realignment in 3D cultures. RNA sequencing of Ror2-deficient organoids further uncovered alterations in actin cytoskeleton, cell adhesion, and collagen crosslinking gene expression programs. Spatially, we pinpoint the upregulation and redistribution of α5 and β3 integrins together with the production of fibronectin in areas of invasion downstream of Ror2 loss. Wnt/β-catenin-dependent and Wnt/Ror2 alternative Wnt signaling appear to regulate distinct functions for tumor cells regarding their ability to modify cell-ECM exchanges during invasion. Furthermore, blocking either integrin or focal adhesion kinase (FAK), a downstream mediator of integrin-mediated signal transduction, abrogates the enhanced migration observed upon Ror2 loss. These results reveal a critical function for the alternative Wnt receptor, Ror2, as a determinant of tumor cell-driven ECM exchanges during cancer invasion and metastasis. [Media: see text] [Media: see text] [Media: see text] [Media: see text]

ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma

“…4A). They also showed a more pronounced stromal reaction with significantly elevated collagen deposition as represented by Picrosirius Red Stain, which was also observed when Ror2 was ablated in a mammary cancer model (Si et al, 2022) (Suppl. Fig.…”

ROR2 regulates cellular plasticity in pancreatic neoplasia and adenocarcinoma

“…Notably, 40 weeks post Tamoxifen, 3 Ptf1a ERT ;K*,Ror2 f/f mice developed regions of carcinoma, a rapidity of progression not observed in our control cohort. They also showed a more pronounced stromal reaction with significantly elevated collagen deposition as represented by Picrosirius Red stain, which was also observed when Ror2 was ablated in a mammary cancer model [39] ( Suppl. Fig.…”

ROR2 promotes invasion and chemoresistance of triple-negative breast cancer cells by activating PI3K/AKT/mTOR signaling

“…Recognized as a noncanonical Wnt receptor, ROR2 regulates a variety of cell activities such as breast cancer cell invasion [ 24 ]. Regulation of ROR2 by siRNA mediated knockdown may inhibit all downstream signaling pathways, including but not limited to PI3K/AKT/mTOR signaling.…”