Cholesterol Biosynthesis Is a Key Feature of Cancer Stem Cells as Revealed by Proteomic Comparison of Breast Cancer Tissue, Corresponding PDXs and Mammospheres
Uniformed Services University of the Health Sciences, Department of Obstetrics & Gynecology, Gynecologic Cancer Center of Excellence, Womens Health Integrated Research Center at Inova Health System; Walter Reed National Military Medical Center
Uniformed Services University of the Health Sciences, Department of Obstetrics & Gynecology, Gynecologic Cancer Center of Excellence, Womens Health Integrated Research Center at Inova Health System; Walter Reed National Military Medical Center
Uniformed Services University of the Health Sciences, Department of Obstetrics & Gynecology, Gynecologic Cancer Center of Excellence, Womens Health Integrated Research Center at Inova Health System; Walter Reed National Military Medical Center; Inova Center for Personalized Health - Inova Schar Cancer Institute
University of Southern Denmark, Institute of Molecular Medicine, Department of Cancer and Inflammation Research; University of Southern Denmark - Department of Regional Health Research
University of Southern Denmark, Institute of Molecular Medicine, Department of Cancer and Inflammation Research; Odense University Hospital, Department of Oncology; Odense University Hospital, Academy of Geriatric Cancer Research (AgeCare)
Cancer stem cells (CSCs) comprise a small subpopulation of undifferentiated cancer cells with the ability to self-renew and give rise to the heterogeneous cancer cell lineages that form tumorous masses. Thus, tumor eradication may be greatly improved by specifically targeting CSCs, as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed patient-derived xenograft (PDX) tumors from ER-negative breast cancer patient tissue from which we isolated mammospheres, a method known to enrich for cells with CSC-properties. An unbiased, comparative global proteomic analysis using label-free mass spectrometry was performed on the patient tumor tissues and corresponding PDX tumors and mammospheres. Good concordance between the proteome profiles of patient versus PDX tumors was observed. However, lower abundance of immune- and extracellular matrix-related proteins and higher abundance of proteins associated with cell-to-cell adhesion including desmosome proteins and β-catenin were observed in PDX versus patient tumors. Interestingly, analysis of proteins elevated in mammospheres vs. PDX tumors identified an enrichment of proteins associated with de novo cholesterol synthesis. The clinical relevance of increased cholesterol biosynthesis was verified in a large breast cancer cohort showing correlation with shorter relapse-free survival. RNA interference and chemical inhibition of the cholesterol biosynthesis pathway reduced mammosphere formation and growth of CSCs derived from PDX tumors and cancer cell lines. Our findings identify the cholesterol biosynthesis pathway as central for CSC propagation and a potential therapeutic target as well as providing mechanistic explanation for the observed benefit of statins in breast cancer treatment.
Ehmsen, Sidse and Pedersen, Martin H. and Wang, Guisong and Terp, Mikkel G. and Arslanagic, Amina and Hood, Brian L. and Conrads, Thomas P. and Leth-Larsen, Rikke and Ditzel, Henrik J., Cholesterol Biosynthesis Is a Key Feature of Cancer Stem Cells as Revealed by Proteomic Comparison of Breast Cancer Tissue, Corresponding PDXs and Mammospheres (November 9, 2018). Available at SSRN: https://ssrn.com/abstract=3281654 or http://dx.doi.org/10.2139/ssrn.3281654
This version of the paper has not been formally peer reviewed.
Uniformed Services University of the Health Sciences, Department of Obstetrics & Gynecology, Gynecologic Cancer Center of Excellence, Womens Health Integrated Research Center at Inova Health System
4301 Jones Bridge Road Bethesda, MD 20814 United States
Walter Reed National Military Medical Center
4494 North Palmer Road Bethesda, MD 20892 United States
Uniformed Services University of the Health Sciences, Department of Obstetrics & Gynecology, Gynecologic Cancer Center of Excellence, Womens Health Integrated Research Center at Inova Health System
4301 Jones Bridge Road Bethesda, MD 20814 United States
Walter Reed National Military Medical Center
4494 North Palmer Road Bethesda, MD 20892 United States
Uniformed Services University of the Health Sciences, Department of Obstetrics & Gynecology, Gynecologic Cancer Center of Excellence, Womens Health Integrated Research Center at Inova Health System
4301 Jones Bridge Road Bethesda, MD 20814 United States
Walter Reed National Military Medical Center
4494 North Palmer Road Bethesda, MD 20892 United States
Inova Center for Personalized Health - Inova Schar Cancer Institute
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