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DDR2 coordinates EMT and metabolic reprogramming as a shared effector of FOXQ1 and SNAI1
Allison V Mitchell1, Jason Wu1,2, Fanyan Meng3
1Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, 4100 John R, Detroit, MI 48201.
Abstract:
While multiple transcription factors (TFs) 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 (HMLE) 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. Lastly, 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.
Insights
FOXQ1 and SNAI1 are independent transcription factors driving epithelial-mesenchymal transition (EMT). They co-regulate DDR2, a receptor tyrosine kinase crucial for cell motility and metabolism in triple-negative breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Epithelial-mesenchymal transition (EMT) is crucial in cancer progression.
- The roles and interactions of transcription factors (TFs) in EMT are not fully understood.
- Understanding TF interdependence is key to targeting cancer metastasis.
Purpose of the Study:
- To investigate the interdependence of FOXQ1 and SNAI1 in EMT.
- To identify shared downstream targets of FOXQ1 and SNAI1.
- To elucidate the role of DDR2 in FOXQ1/SNAI1-driven EMT and triple-negative breast cancer (TNBC).
Main Methods:
- Analysis of transcription factor interactions in EMT models.
- Gene expression profiling and coexpression signature analysis.
- Functional assays assessing cell motility, morphology, and stem cell populations.
- Metabolic profiling following DDR2 knockdown.
Main Results:
- FOXQ1 and SNAI1 function independently in EMT, upregulating common EMT TFs without reciprocal influence.
- DDR2 is identified as a shared downstream effector of FOXQ1 and SNAI1, and the most upregulated receptor tyrosine kinase in TNBC.
- DDR2 alteration profoundly impacts cell motility but not EMT markers, morphology, or stem cell populations.
- DDR2 knockdown significantly alters global metabolism, including amino acid recycling.
Conclusions:
- FOXQ1 and SNAI1 are independent drivers of EMT with a shared mechanism involving DDR2.
- DDR2 plays a critical role in regulating cell motility and metabolism downstream of FOXQ1 and SNAI1 in TNBC.
- Targeting DDR2 may offer a therapeutic strategy for modulating TNBC cell motility and metabolism.
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