RON ( MST1R) and HGFL ( MST1) Co-Overexpression Supports Breast Tumorigenesis through Autocrine and Paracrine Cellular Crosstalk

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.