Abstract
The loss of E-cadherin (E-cad), an epithelial cell adhesion molecule, has been implicated in the epithelial-mesenchymal transition (EMT), promoting invasion and migration of cancer cells and, consequently, metastasis. However, recent studies have demonstrated that E-cad supports the survival and proliferation of metastatic cancer cells, suggesting that our understanding of E-cad in metastasis is far from comprehensive. Here, we report that E-cad upregulates the de novo serine synthesis pathway (SSP) in breast cancer cells. The SSP provides metabolic precursors for biosynthesis and resistance to oxidative stress, critically beneficial for E-cad-positive breast cancer cells to achieve faster tumor growth and more metastases. Inhibition of PHGDH, a rate- limiting enzyme in the SSP, significantly and specifically hampered the proliferation of E-cad- positive breast cancer cells and rendered them vulnerable to oxidative stress, inhibiting their metastatic potential. Our findings reveal that E-cad adhesion molecule significantly reprograms cellular metabolism, promoting tumor growth and metastasis of breast cancers.
Competing Interest Statement
A.J.E. is an inventor of unlicensed patents covering the use of antibodies as cancer therapeutics and the use of keratin-14 as a prognostic indicator for breast cancer outcomes. Spouse of A.J.E. is an employee of ImmunoCore. R.D.L. is an inventor of patents covering the use of glutamine antagonist prodrugs, which have been licensed to Dracen Pharmaceuticals, and is a consultant to Mitobridge/Astellas.