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Nat Commun ; 11(1): 1533, 2020 03 24.
Article in English | MEDLINE | ID: mdl-32210228

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.


Subject(s)
Cell Movement/drug effects , Glucose Transporter Type 1/metabolism , Lung Neoplasms/pathology , Pyruvate Dehydrogenase (Lipoamide)/metabolism , Animals , Cell Communication/drug effects , Cell Line, Tumor , Cell Proliferation , Gene Knockdown Techniques , Glucose/metabolism , Glucose Transporter Type 1/antagonists & inhibitors , Glucose Transporter Type 1/genetics , Humans , Lung Neoplasms/drug therapy , Mice , Neoplasm Invasiveness/pathology , Neoplasm Invasiveness/prevention & control , Oxidative Phosphorylation , Pyruvate Dehydrogenase (Lipoamide)/antagonists & inhibitors , Pyruvate Dehydrogenase (Lipoamide)/genetics , RNA, Small Interfering/metabolism , Spheroids, Cellular
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