DDR2 Coordinates EMT and Metabolic Reprogramming as a Shared Effector of FOXQ1 and SNAI1

Abstract

While multiple transcription factors (TF) have been recognized to drive epithelial–mesenchymal transition (EMT) in cancer, their interdependence and context-dependent functions are poorly understood. In this study, we show that FOXQ1 and SNAI1 act as independent TFs within the EMT program with a shared ability to upregulate common EMT-TFs without reciprocally impacting the expression of one another. Despite this independence, human mammary epithelial cells with ectopic expression of either FOXQ1 or SNAI1 share a common gene set that is enriched for a DDR2 coexpression signature. Further analysis identified DDR2 as the most upregulated receptor tyrosine kinase and a shared downstream effector of FOXQ1 and SNAI1 in triple-negative breast cancer (TNBC) cell lines. Alteration of DDR2 expression in either FOXQ1- or SNAI1-driven EMT models or in TNBC cells resulted in a profound change of cell motility without significantly impacting EMT marker expression, cell morphology, or the stem cell population. Finally, we demonstrated that knockdown of DDR2 in the FOXQ1-driven EMT model and TNBC cell line significantly altered the global metabolic profile, including glutamine-glutamate and aspartic acid recycling. Significance: The critical role of DDR2 in cancer metastasis has been well established. However, the exact function of DDR2 in driving cancer metastatic progression remains unclear. The results of our current study provide new insights into the cancer-driving function of DDR2, suggesting that DDR2, as a shared effector of the EMT program, may drive tumor progression by promoting breast cancer cell motility and metabolic reprogramming.