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

SIMPLE SUMMARY: RON is a protein that sits on the surface of a cell and passes signals from the outside-in when encountering the HGFL protein. In cancer, the RON protein is often found at high levels leading to too many signals being passed. Given the close proximity of RON and HGFL in the human genome, we hypothesized that the two proteins are overproduced together in cancer cells. Other cells that interact with cancer cells, such as macrophages, also express RON and can respond to HGFL produced by cancer cells, creating a diverse response to overly abundant RON and HGFL. In this study, we evaluated how RON and HGFL in cancer cells affect cancer growth and progression and their response to other cells, and examined explanations for increases in RON and HGFL abundance in breast cancer. ABSTRACT: 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.