Metabolic stress induces GD2+ cancer stem cell-like phenotype in triple-negative breast cancer

• Published in: British journal of cancer Vol. 126; no. 4; pp. 615 - 627
• Main Authors: Jaggupilli, Appalaraju, Ly, Stanley, Nguyen, Khoa, Anand, Vivek, Yuan, Bin, El-Dana, Fouad, Yan, Yuanqing, Arvanitis, Zoe, Piyarathna, Danthasinghe Waduge Badrajee, Putluri, Nagireddy, Piwnica-Worms, Helen, Manning, Henry Charles, Andreeff, Michael, Battula, V. Lokesh
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.03.2022; Nature Publishing Group
• Subjects: 631/67/1347; 631/80/83; Animals; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Blood Glucose - analysis; Breast cancer; Cancer Research; Cell Line, Tumor; Chemotherapy; Diabetes mellitus; Drug Resistance; Epidemiology; Female; Ferroptosis; Ferroptosis - drug effects; Flow cytometry; Gangliosides - metabolism; Genotype & phenotype; Glutamine; Glutamine - metabolism; Glutathione; Humans; Interleukin 2; Interleukin 2 receptors; Mass spectroscopy; Metabolism; Metabolomics; Metabolomics - methods; Mice; Molecular Medicine; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nutrient deficiency; Oncology; Phenotype; Phenotypes; Severe combined immunodeficiency; Small Molecule Libraries - administration & dosage; Small Molecule Libraries - pharmacology; Stem cells; TOR protein; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumorigenesis; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-021-01636-y

Background Metabolic stress resulting from nutrient deficiency is one of the hallmarks of a growing tumour. Here, we tested the hypothesis that metabolic stress induces breast cancer stem-like cell (BCSC) phenotype in triple-negative breast cancer (TNBC). Methods Flow cytometry for GD2 expression, mass spectrometry and Ingenuity Pathway Analysis for metabolomics, bioinformatics, in vitro tumorigenesis and in vivo models were used. Results Serum/glucose deprivation not only increased stress markers but also enhanced GD2 + BCSC phenotype and function in TNBC cells. Global metabolomics profiling identified upregulation of glutathione biosynthesis in GD2 high cells, suggesting a role of glutamine in the BCSC phenotype. Cueing from the upregulation of the glutamine transporters in primary breast tumours, inhibition of glutamine uptake using small-molecule inhibitor V9302 reduced GD2 + cells by 70–80% and BCSC characteristics in TNBC cells. Mechanistic studies revealed inhibition of the mTOR pathway and induction of ferroptosis by V9302 in TNBC cells. Finally, inhibition of glutamine uptake significantly reduced in vivo tumour growth in a TNBC patient-derived xenograft model using NSG (non-obese diabetic/severe combined immunodeficiency with a complete null allele of the IL-2 receptor common gamma chain) mice. Conclusion Here, we show metabolic stress results in GD2 + BCSC phenotype in TNBC and glutamine contributes to GD2 + phenotype, and targeting the glutamine transporters could complement conventional chemotherapy in TNBC.