HGFL-mediated RON signaling supports breast cancer stem cell phenotypes via activation of non-canonical β-catenin signaling

Breast cancer stem cells (BCSCs), which drive tumor progression, recurrence, and metastasis, are considered a major challenge for breast cancer treatments, thus the discovery of novel pathways regulating BCSC maintenance remains essential to develop new strategies to effectively target this population and combat disease mortality. The HGFL-RON signaling is overexpressed in human breast cancers and is associated with increased breast cancer progression, metastasis, and poor prognosis. Here, we report that overexpression of RON/MST1R and HGFL/MST1 in cell lines and primary tumors increases BCSC self-renewal, numbers, and tumorigenic potential after syngeneic transplantation. Transcriptome analyses also reveal that the HGFL-RON signaling pathway regulates additional BCSC functions and supports an immunosuppressive microenvironment to stimulate tumor formation and progression. Moreover, we show that genetic and chemical downregulation of HGFL-RON signaling disrupts BCSC phenotypes and tumor growth by suppressing the RON-mediated phosphorylation/activation of β-CATENIN/CTNNB1 and its effector NF-κB/RELA. These studies indicate that HGFL-RON signaling regulates BCSC phenotypes and the tumor microenvironment to drive tumorigenesis and present HGFL/RON as novel therapeutic targets to effectively eradicate BCSCs in patients.