Fatty acid synthesis is required for breast cancer brain metastasis

Abstract

AUTHOR CONTRIBUTIONS G.F., A.A. and A.L. performed experiments and helped analyze all data with supervision from R.K.J. and M.G.V.H. D.P.K., D.B. and D.F. contributed in identifying metabolic signatures of brain metastasis; K.LA. and A.W. contributed to in vitro work and GCMS analysis. A.D. and C.B.C. performed LCMS lipidomics and helped with analysis; L.B., B.P. and V.A.D performed IMS imaging and analysis; X.J. and T.R.G. contributed to extracellular fluid isolation and provided input on data interpretation. J.M.P., N.I.L. and E.B. collected clinical samples and contributed to analysis of patient tumor sections; J.C. and D.G.D. performed ultrasound imaging of liver tumors; C.R.C. and S.M.D. contributed to in vivo glucose tracing studies. Z.A. performed flow cytometry analysis. R.F. and J.N. helped with analysis of lipidomics data. I.C., C.N. and D.E.H. analyzed human expression databases. K.N. performed analysis of Affymetrix array. M.D. and S.R. contributed to CRISPR Cas9 methodology and animal implantations.

Aberrant Metabolism as Inductor of Epigenetic Changes in Breast Cancer: Therapeutic Opportunities

“…The role of lipid membranes in sustaining high rates of cell replication in the tumor mass is evident; however, other functions of key enzymes in lipid biosynthesis have been characterized. Fatty acid synthase (FASN) catalyzes palmitate biosynthesis using acetyl-CoA and malonyl-CoA in the presence of NADPH; FASN is overexpressed in treatment-resistant mammary tumors (49,50), and fatty acid syntheses are increased in brain metastases in mammary tumors (51). Other functions of FASN in addition to lipid synthesis are mainly associated with oncogenic signaling derived from tyrosine receptor kinases; it has been described that FASN can be directly phosphorylated by HER2, leading to the increased enzymatic activity of FASN enhancing tumor cell invasion and migration (52).…”

BNIP3 attenuates hepatocellular carcinoma by promoting lipid droplet turnover at the lysosome.

“…Increased lipid synthesis may promote tumor cell growth by fueling triglyceride formation for cell membranes and signaling, amongst other functions 27 . Interestingly, breast cancer cells are particularly dependent on fatty acid synthesis after metastasizing to the brain which has limited fatty acid availability compared to either the primary site or other metastatic sites 57 . These studies have driven efforts to target FASN and ACACA enzymes for therapeutic benefit 43,55,[58][59][60] .…”

Fatty Acid Synthesis in Prostate Cancer: Vulnerability or Epiphenomenon?

“…While these data suggest that de novo fatty acid synthesis occurs in human prostate cancer, and with increasing rate with disease progression (Figure 2D), this could be assessed more definitively using isotope tracing followed by assessment of labeling patterns by mass spectrometry in biopsy samples of patients, as has been performed in patients with renal cell carcinoma (43). Moreover, given that cellular metabolic flux is shaped by both cell-intrinsic factors and the microenvironment (44), future studies should consider how prostate cancer cell rates of fatty acid synthesis are altered depending on composition of surrounding cell types (i.e. anatomic location of the metastasis) and metabolite and oxygen availability.…”