E-Cadherin Induces Serine Synthesis to Support Progression and Metastasis of Breast Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 84; no. 17; pp. 2820 - 2835
• Main Authors: Lee, Geonhui, Wong, Claudia, Cho, Anna, West, Junior J, Crawford, Ashleigh J, Russo, Gabriella C, Si, Bishwa R, Kim, Jungwoo, Hoffner, Lauren, Jang, Cholsoon, Jung, Moonjung, Leone, Robert D, Konstantopoulos, Konstantinos, Ewald, Andrew J, Wirtz, Denis, Jeong, Sangmoo
• Format: Journal Article
• Language: English
• Published: United States 04.09.2024
• Subjects: Animals; Antigens, CD - metabolism; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cadherins - metabolism; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Epithelial-Mesenchymal Transition; Female; Humans; Mice; Mice, Nude; Neoplasm Metastasis; Oxidative Stress; Phosphoglycerate Dehydrogenase - genetics; Phosphoglycerate Dehydrogenase - metabolism; Serine - metabolism
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-23-3082

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.