Abstract:
:An improved understanding of the biochemical alterations that accompany tumor progression and metastasis is necessary to inform the next generation of diagnostic tools and targeted therapies. Metabolic reprogramming is known to occur during the epithelial-mesenchymal transition (EMT), a process that promotes metastasis. Here, we identify metabolic enzymes involved in extracellular matrix remodeling that are upregulated during EMT and are highly expressed in patients with aggressive mesenchymal-like breast cancer. Activation of EMT significantly increases production of hyaluronic acid, which is enabled by the reprogramming of glucose metabolism. Using genetic and pharmacological approaches, we show that depletion of the hyaluronic acid precursor UDP-glucuronic acid is sufficient to inhibit several mesenchymal-like properties including cellular invasion and colony formation in vitro, as well as tumor growth and metastasis in vivo. We found that depletion of UDP-glucuronic acid altered the expression of PPAR-gamma target genes and increased PPAR-gamma DNA-binding activity. Taken together, our findings indicate that the disruption of EMT-induced metabolic reprogramming affects hyaluronic acid production, as well as associated extracellular matrix remodeling and represents pharmacologically actionable target for the inhibition of aggressive mesenchymal-like breast cancer progression.
journal_name
Oncogenejournal_title
Oncogeneauthors
Arnold JM,Gu F,Ambati CR,Rasaily U,Ramirez-Pena E,Joseph R,Manikkam M,San Martin R,Charles C,Pan Y,Chatterjee SS,Den Hollander P,Zhang W,Nagi C,Sikora AG,Rowley D,Putluri N,Zhang XH,Karanam B,Mani SA,Sreekumar Adoi
10.1038/s41388-019-0885-4subject
Has Abstractpub_date
2020-04-01 00:00:00pages
3089-3101issue
15eissn
0950-9232issn
1476-5594pii
10.1038/s41388-019-0885-4journal_volume
39pub_type
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