| First Author | Hunt BG | Year | 2022 |
| Journal | Cancers (Basel) | Volume | 14 |
| Issue | 10 | PubMed ID | 35626096 |
| Mgi Jnum | J:350087 | Mgi Id | MGI:7661275 |
| Doi | 10.3390/cancers14102493 | Citation | Hunt BG, et al. (2022) RON (MST1R) and HGFL (MST1) Co-Overexpression Supports Breast Tumorigenesis through Autocrine and Paracrine Cellular Crosstalk. Cancers (Basel) 14(10) |
| abstractText | BACKGROUND: Aberrant RON signaling is present in numerous cancers including breast cancer. Evidence suggests that the ligand, hepatocyte growth factor-like (HGFL), is also overexpressed in breast cancer. RON (MST1R) and HGFL (MST1) genes are located on human chromosome 3 and mouse chromosome 9 respectively and are found near each other in both species. Based on co-expression patterns, we posited that RON and HGFL are co-regulated and that coordinate upregulation drives aggressive tumorigenesis. METHODS: Mouse models were used to establish the functional significance of RON and HGFL co-overexpression on the activation of tumor cells and tumor-associated macrophages in breast cancer. TCGA and METABRIC gene expression and alteration data were used to query the relationships between MST1R and MST1 in breast cancer. RESULTS: In tumor models, physiologic sources of HGFL modestly improve Arginase-1(+) (M2) macrophage recruitment to the tumor proper. Tumor-cell produced HGFL functions in autocrine to sustain tumor cell RON activation and MAPK-dependent secretion of chemotactic factors and in paracrine to activate RON on macrophages and to promote breast cancer stem cell self-renewal. In silico analyses support that RON and HGFL are co-expressed across virtually all cancer types including breast cancer and that common genomic alterations do not appear to be drivers of RON/HGFL co-overexpression. CONCLUSIONS: Co-overexpression of RON and HGFL in breast cancer cells (augmented by physiologic sources of HGFL) promotes tumorigenesis through autocrine-mediated RON activation/RON-dependent secretome changes and paracrine activation of macrophage RON to promote breast cancer stem cell self-renewal. |
