Tuberous sclerosis complex (
TSC) is an autosomal dominant disease characterized by multiorgan
hamartomas, including renal
angiomyolipomas and pulmonary
lymphangioleiomyomatosis (
LAM). TSC2 deficiency leads to hyperactivation of mTOR Complex 1 (
mTORC1), a master regulator of cell growth and metabolism.
Phospholipid metabolism is dysregulated upon TSC2 loss, causing enhanced production of
lysophosphatidylcholine (LPC) species by TSC2-deficient
tumor cells. LPC is the major substrate of the secreted
lysophospholipase D autotaxin (ATX), which generates two bioactive
lipids,
lysophosphatidic acid (LPA) and
sphingosine-1-phosphate (S1P). We report here that ATX expression is upregulated in human renal
angiomyolipoma-derived TSC2-deficient cells compared with TSC2 add-back cells. Inhibition of ATX via the clinically developed compound
GLPG1690 suppressed TSC2-loss associated oncogenicity in vitro and in vivo and induced apoptosis in TSC2-deficient cells.
GLPG1690 suppressed AKT and ERK1/2 signaling and profoundly impacted the transcriptome of these cells while inducing minor gene expression changes in TSC2 add-back cells.
RNA-sequencing studies revealed transcriptomic signatures of LPA and S1P, suggesting an LPA/S1P-mediated reprogramming of the
TSC lipidome. In addition, supplementation of LPA or S1P rescued proliferation and viability, neutral
lipid content, and AKT or ERK1/2 signaling in human TSC2-deficient cells treated with
GLPG1690. Importantly,
TSC-associated renal
angiomyolipomas have higher expression of
LPA receptor 1 and
S1P receptor 3 compared with normal kidney. These studies increase our understanding of TSC2-deficient cell metabolism, leading to novel potential therapeutic opportunities for
TSC and
LAM. SIGNIFICANCE: This study identifies activation of the ATX-LPA/S1P pathway as a novel mode of metabolic dysregulation upon TSC2 loss, highlighting critical roles for ATX in TSC2-deficient cell fitness and in
TSC tumorigenesis.