Secreted Factors from Adipose Tissue Reprogram Tumor Lipid Metabolism and Induce Motility by Modulating PPARα/ANGPTL4 and FAK

Mol Cancer Res. 2020 Dec;18(12):1849-1862. doi: 10.1158/1541-7786.MCR-19-1223. Epub 2020 Aug 28.

Abstract

Recent studies indicate that adipose tissue in obesity promotes breast cancer progression by secreting protumorigenic chemokines, growth factors, and fatty acids. However, the detailed mechanisms by which hypertrophic adipose tissue influences breast cancer cells are still not well understood. Here we show that co-culture with adipose tissue from high-fat diet induced obese C57BL/6 mice alters transcriptome profiles in triple-negative breast cancer (TNBC) cells, leading to upregulation of genes involved in inflammation and lipid metabolism, such as IL1B, PLIN2, and ANGPTL4. Similar results were obtained by treating TNBC cells with adipose tissue conditioned media (ACM) generated from fat tissue of obese female patients. Many of the upregulated genes were activated by PPAR nuclear receptors, as shown by pathway analyses and gene expression experiments using PPAR agonists and antagonists. Metabolic analysis revealed that TNBC cells cultivated with ACM had significantly higher levels of β-oxidation. Furthermore, ACM-treated TNBC cells displayed a pronounced aggressive cell phenotype, with enhanced wound healing, proliferation, and invasion capabilities. ACM-induced invasion was dependent on the PPAR-target ANGPTL4 and activated FAK signaling, as shown by ANGPTL4 depletion and FAK inhibition. Together, our data suggest that factors released by adipose tissue change PPAR-regulated gene expression and lipid metabolism and induce a more aggressive TNBC cell phenotype. These effects are, at least in parts, mediated by fatty acids provided by the adipose tissue. IMPLICATIONS: Adipose tissue provides factors for increased progression of TNBC cells, identifying PPAR- and FAK-signaling as potential novel targets for treatment of TNBC, especially in obese women.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / cytology*
  • Adipose Tissue / metabolism
  • Angiopoietin-like 4 Protein / genetics
  • Angiopoietin-like 4 Protein / metabolism*
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Coculture Techniques
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Female
  • Focal Adhesion Kinase 1 / genetics
  • Focal Adhesion Kinase 1 / metabolism*
  • Gene Expression Regulation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lipid Metabolism
  • Mice
  • Obesity / chemically induced
  • Obesity / complications
  • Obesity / genetics
  • Obesity / metabolism*
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*

Substances

  • ANGPTL4 protein, human
  • Angiopoietin-like 4 Protein
  • PPAR alpha
  • PPARA protein, human
  • Focal Adhesion Kinase 1
  • PTK2 protein, human