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1.
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
2.
Nat Commun ; 8: 15078, 2017 05 12.
Article in English | MEDLINE | ID: mdl-28497793

ABSTRACT

Phenotypic heterogeneity is widely observed in cancer cell populations. Here, to probe this heterogeneity, we developed an image-guided genomics technique termed spatiotemporal genomic and cellular analysis (SaGA) that allows for precise selection and amplification of living and rare cells. SaGA was used on collectively invading 3D cancer cell packs to create purified leader and follower cell lines. The leader cell cultures are phenotypically stable and highly invasive in contrast to follower cultures, which show phenotypic plasticity over time and minimally invade in a sheet-like pattern. Genomic and molecular interrogation reveals an atypical VEGF-based vasculogenesis signalling that facilitates recruitment of follower cells but not for leader cell motility itself, which instead utilizes focal adhesion kinase-fibronectin signalling. While leader cells provide an escape mechanism for followers, follower cells in turn provide leaders with increased growth and survival. These data support a symbiotic model of collective invasion where phenotypically distinct cell types cooperate to promote their escape.


Subject(s)
Cell Movement/genetics , Genetic Heterogeneity , Genomics/methods , Spheroids, Cellular/metabolism , Cell Communication/genetics , Cell Line, Tumor , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Invasiveness , Neoplasms/blood supply , Neoplasms/genetics , Neoplasms/pathology , Phenotype , Spheroids, Cellular/pathology , Tumor Microenvironment/genetics , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
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