Intra-tumour heterogeneity is a great challenge in cancer treatment. Cancer cells presenting different metabolic profiles can mutually support each other through metabolic symbiosis mechanism, which contributes to tumour proliferation, metastasis, and therapeutic resistance. Triple-negative breast cancer (TNBC) shows poor clinical outcomes due to a high level of heterogeneity and a lack of targeted therapies. Through multiplex immunofluorescence tissue section staining of TNBC patient-derived xenografts (PDX), we identified two mutually exclusive and metabolically distinct cell populations within a TNBC tumour. One cancer cell population expresses glucose transporter 1 (GLUT1) and is located in hypoxic areas, whereas another specifically expresses glutamine synthetase (GS) and is located near vasculatures. Single-cell RNA sequencing data from a TNBC PDX with mutually exclusive GLUT1- and GS-positive cells shows that GLUT1-positive cells are enriched for hypoxic and glycolytic gene signatures, while GS-positive cells are associated with glutathione, pyrimidine and purine metabolism. Importantly, our data suggest that GLUT1- and GS-positive cells exchange glutamate and lactate metabolites as part of metabolic symbiosis and targeting this mechanism could successfully impair the growth of TNBC.

Citation Format: Marina Fukano, Geneviève Deblois, Dongmei Zuo, Constanza Martinez, Yang Yang, Ioannis Ragoussis, Claudia Kleinman, Morag Park. Investigating intra-tumour metabolic heterogeneity in triple-negative breast cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-053.