Continuous inflammatory stimulation leads via metabolic plasticity to a prometastatic phenotype in triple‐negative breast cancer cells

Dina Morein, Linor Rubinstein‐achiasaf, Hadar Brayer, Orly Dorot, Edward Pichinuk, Hagar Ben‐yaakov, Tsipi Meshel, Metsada Pasmanik‐chor, Adit Ben‐baruch

Research output: Contribution to journalArticlepeer-review

Abstract

Chronic inflammation promotes cancer progression by affecting the tumor cells and their microenvironment. Here, we demonstrate that a continuous stimulation (~6 weeks) of triple‐nega-tive breast tumor cells (TNBC) by the proinflammatory cytokines tumor necrosis factor α (TNFα) + interleukin 1β (IL‐1β) changed the expression of hundreds of genes, skewing the cells towards a proinflammatory phenotype. While not affecting stemness, the continuous TNFα + IL‐1β stimulation has increased tumor cell dispersion and has induced a hybrid metabolic phenotype in TNBC cells; this phenotype was indicated by a transcription‐independent elevation in glycolytic activity and by increased mitochondrial respiratory potential (OXPHOS) of TNBC cells, accompanied by elevated transcription of mitochondria‐encoded OXPHOS genes and of active mitochondria area. The continuous TNFα + IL‐1β stimulation has promoted in a glycolysis‐dependent manner the activation of p65 (NF‐κB), and the transcription and protein expression of the prometastatic and pro-inflammatory mediators sICAM‐1, CCL2, CXCL8 and CXCL1. Moreover, when TNBC cells were stimulated continuously by TNFα + IL‐1β in the presence of a glycolysis inhibitor, their conditioned media had reduced ability to recruit monocytes and neutrophils in vivo. Such inflammation‐in-duced metabolic plasticity, which promotes prometastatic cascades in TNBC, may have important clinical implications in treatment of TNBC patients.

Original languageEnglish
Article number1356
JournalCells
Volume10
Issue number6
DOIs
StatePublished - Jun 2021

Keywords

  • Glycolysis
  • Inflammation
  • Interleukin 1β
  • Leukocyte migration
  • Metabolism
  • Oxidative phosphorylation
  • Triple‐negative breast cancer
  • Tumor necrosis factor α

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