Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion

• Type of Material: Article
• Authors: R. Commander, Emory University; Chungwen Wei, Emory University; A. Sharma, Emory University; J. K. Mouw, Emory University; Laurie Burton, Emory University; E. Summerbell, Emory University; D. Mahboubi, Emory University; R. J. Peterson, Emory University; J. Konen, Univ Texas MD Anderson Canc Ctr; Wei Zhou, Emory University; Yuhong Du, Emory University; Haian Fu, Emory University; Malathy Shanmugam, Emory University; Adam Marcus, Emory University
• Language: English
• Date: 2020-03-24
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2020, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-15219-7
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 1533
• End Page: 1533
• Keywords: Tumor heterogeneity; Intratumor heterogeneity; Plasticity; TCA cycle; Science & Technology; Multidisciplinary Sciences; Lung cancer; Mitchondria; Science & Technology - Other Topics; Expression; Metastasis; Glucose; Identification
• Research Categories: Biology, Cell; Chemistry, Biochemistry; Health Sciences, Immunology; Health Sciences, Oncology

Abstract

Phenotypic heterogeneity exists within collectively invading packs of tumor cells, suggesting that cellular subtypes cooperate to drive invasion and metastasis. Here, we take a chemical biology approach to probe cell:cell cooperation within the collective invasion pack. These data reveal metabolic heterogeneity within invasive chains, in which leader cells preferentially utilize mitochondrial respiration and trailing follower cells rely on elevated glucose uptake. We define a pyruvate dehydrogenase (PDH) dependency in leader cells that can be therapeutically exploited with the mitochondria-targeting compound alexidine dihydrochloride. In contrast, follower cells highly express glucose transporter 1 (GLUT1), which sustains an elevated level of glucose uptake required to maintain proliferation. Co-targeting of both leader and follower cells with PDH and GLUT1 inhibitors, respectively, inhibits cell growth and collective invasion. Taken together, our work reveals metabolic heterogeneity within the lung cancer collective invasion pack and provides rationale for co-targeting PDH and GLUT1 to inhibit collective invasion.