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

Author:

Lee Geonhui12ORCID,Wong Claudia12ORCID,Cho Anna12ORCID,West Junior J.3ORCID,Crawford Ashleigh J.12ORCID,Russo Gabriella C.12ORCID,Si Bishwa R.12ORCID,Kim Jungwoo4ORCID,Hoffner Lauren5ORCID,Jang Cholsoon5ORCID,Jung Moonjung467ORCID,Leone Robert D.8ORCID,Konstantopoulos Konstantinos1297ORCID,Ewald Andrew J.397ORCID,Wirtz Denis127ORCID,Jeong Sangmoo127ORCID

Affiliation:

1. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland. 1

2. Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland. 2

3. Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, Maryland. 3

4. Division of Hematology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland. 4

5. Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, California. 5

6. Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland. 6

7. Department of Oncology, Sidney Kimmel Comprehensive Cancer Research Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland. 9

8. Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland. 7

9. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland. 8

Abstract

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.

Funder

National Institutes of Health

Maryland Stem Cell Research Fund

Breast Cancer Research Foundation

METAvivor

Jayne Koskinas Ted Giovanis Foundation for Health and Policy

American Association for the Study of Liver Diseases

Edward Mallinckrodt, Jr. Foundation

Publisher

American Association for Cancer Research (AACR)

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