Serine synthesis pathway upregulated by E-cadherin is essential for the proliferation and metastasis of breast cancers
Lee, G.; Wong, C.; Cho, A.; West, J. J.; Crawford, A. J.; Russo, G. C.; Si, B. R.; Kim, J.; Hoffner, L.; Jang, C.; Jung, M.; Leone, R. D.; Konstantopoulos, K.; Ewald, A. J.; Wirtz, D.; Jeong, S.
Show 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.
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