E-Cadherin Induces Serine Synthesis to Support Progression and Metastasis of Breast Cancer
Geonhui Lee, Claudia Wong, Anna Cho, Junior J. West, Ashleigh J. Crawford, Gabriella C. Russo, R. Bishwa, Jung-Woo Kim, Lauren Hoffner, Cholsoon Jang, Moonjung Jung, Robert D. Leone, Κωνσταντίνος Κωνσταντόπουλος, Andrew J. Ewald, Denis Wirtz, Sangmoo Jeong
Abstract
The loss of E-cadherin, an epithelial cell adhesion molecule, has been implicated in metastasis by mediating the epithelial-mesenchymal transition, which promotes invasion and migration of cancer cells. However, recent studies have demonstrated that E-cadherin supports the survival and proliferation of metastatic cancer cells. Here, we identified a metabolic role for E-cadherin in breast cancer by upregulating the de novo serine synthesis pathway (SSP). The upregulated SSP provided metabolic precursors for biosynthesis and resistance to oxidative stress, enabling E-cadherin+ breast cancer cells to achieve faster tumor growth and enhanced metastases. Inhibition of phosphoglycerate dehydrogenase, a rate-limiting enzyme in the SSP, significantly and specifically hampered proliferation of E-cadherin+ breast cancer cells and rendered them vulnerable to oxidative stress, inhibiting their metastatic potential. These findings reveal that E-cadherin reprograms cellular metabolism, promoting tumor growth and metastasis of breast cancers. Significance: E-Cadherin promotes the progression and metastasis of breast cancer by upregulating the de novo serine synthesis pathway, offering promising targets for inhibiting tumor growth and metastasis in E-cadherin-expressing tumors.