Functional characterization of nuclear receptor NR1D1 on investigation of brain metastasis

Abstract

Brain metastasis is a fatal recurrence of advanced cancer that affects 20% of cancer patients. Capturing comprehensive brain metastasis landscape is critical to the establishment of sufficient and effective anti-tumor strategies. Ongoing research efforts in our team aim to better understand the biology of tumor cells in human brain metastasis. Preliminary data, generated by single cell sequencing of human brain metastases highlighted a potential role of the nuclear receptor NR1D1. Indeed, NR1D1 activity seems to be correlated with proliferation, immune evasion, and metabolism of brain metastatic tumor cells. The activity of this nuclear receptor can be controlled by its ligand Hemin (HEME) and is critical in retaining control of the circadian rhythm. Our aim is to investigate the functional properties of NR1D1 itself through breast cancer cell lines. Breast cancer cell lines, SUM190, MDA-MB-231 and JIMT1 were used to study NR1D1 function and undergone multiple treatments with conditions that consisted of exposing HEME and a synthetic agonist in various incubation times while adjusting media with no FBS, essentially starving the cells from creating their own HEME. In publicly available data sets it was found that low NR1D1 expression correlated with increase of Triradylglcerols metabolism and high NR1D1 expression with increase of amino acids and peptide metabolism. In addition, our data suggests that NR1D1 activation leads to cell morphology changes and future experiments will determine whether NR1D1 influences tumor cell proliferation and immune invasion. This will assist in determining discrete phenotypes of brain metastatic tumor cells and new approaches for treatment.