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

• Published in: Cancers Vol. 14; no. 10; p. 2493
• Main Authors: Hunt, Brian G, Jones, Angelle, Lester, Carissa, Davis, James C, Benight, Nancy M, Waltz, Susan E
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19.05.2022; MDPI
• Subjects: Animal models; Arginase; Autocrine signalling; Bone marrow; Breast cancer; Cell activation; Cell self-renewal; Cell surface; Chemotactic factors; Chromosome 3; Chromosome 9; Gene expression; Genes; Hepatocyte growth factor; Kinases; Laboratories; Ligands; Macrophages; MAP kinase; Metastasis; Mutation; Paracrine signalling; Ron protein; Secretome; Stem cells; Tumor cells; Tumorigenesis; Tumors; United States > US; breast tumorigenesis; macrophage activation; tumor microenvironment; receptor tyrosine kinases
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14102493

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 ( ) and HGFL ( ) 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. 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 and in breast cancer. 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. 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.