Sugar rush
Metabolic changes within the tumor microenvironment include increased glycolysis; however, it not clear if enhanced glycolytic activity is the result of tumorigenesis or an oncogenic-driving event. Using a 3-dimensional cell culture system (lrECM) to evaluate the role of aerobic glycolysis in breast cancer cells, Yasuhito Onodera, Jin-Min Nam, and Mina Bissell revealed that increased sugar uptake by mammary cells promotes oncogenesis, rather than being a cancer-induced metabolic change. Overexpression of glucose transporter 3 (GLUT3) in non-malignant human breast cells activated known oncogenic pathways, resulting in a loss of tissue polarity, and increased cell replication. In contrast, reduction of glucose uptake in malignant breast cancer cells restored tissue organization and suppressed oncogenic signaling. Furthermore, the authors revealed that glucose-dependent upregulation of EPAC/RAP1 and O-linked N-acetylglucosamine pathways drive cancer-associated phenotypes. In the accompanying image, non-malignant S1 cells (top left) and malignant T4-2 cells (top right) show no difference in organization when cultured in 2D; however, S1 cells cultured in lrECM (bottom left) exhibit a polarized structure, while T4-2 cells cultured in lrECM exhibit a disorganized structure as seen with staining for alpha-6 integrin (green), beta-actin (red) and DAPI (blue).
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Abstract
There is a considerable resurgence of interest in the role of aerobic glycolysis in cancer; however, increased glycolysis is frequently viewed as a consequence of oncogenic events that drive malignant cell growth and survival. Here we provide evidence that increased glycolytic activation itself can be an oncogenic event in a physiologically relevant 3D culture model. Overexpression of glucose transporter type 3 (GLUT3) in nonmalignant human breast cells activated known oncogenic signaling pathways, including EGFR, β1 integrin, MEK, and AKT, leading to loss of tissue polarity and increased growth. Conversely, reduction of glucose uptake in malignant cells promoted the formation of organized and growth-arrested structures with basal polarity, and suppressed oncogenic pathways. Unexpectedly and importantly, we found that unlike reported literature, in 3D the differences between “normal” and malignant phenotypes could not be explained by HIF-1α/2α, AMPK, or mTOR pathways. Loss of epithelial integrity involved activation of RAP1 via exchange protein directly activated by cAMP (EPAC), involving also O-linked N-acetylglucosamine modification downstream of the hexosamine biosynthetic pathway. The former, in turn, was mediated by pyruvate kinase M2 (PKM2) interaction with soluble adenylyl cyclase. Our findings show that increased glucose uptake activates known oncogenic pathways to induce malignant phenotype, and provide possible targets for diagnosis and therapeutics.
Authors
Yasuhito Onodera, Jin-Min Nam, Mina J. Bissell
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)