TSC2 Reconstitution Suggests a Lymphatic Endothelial Origin of Angiomyolipoma Cells

Angiomyolipoma (AML) is a member of the perivascular epithelioid cell tumor (PEComa) family, which is characterized by the proliferation of smooth muscle α-actin (SMA) and melanocytic protein gp100 positive spindle-shaped and epithelioid cells mainly in the kidney. AML and Lymphangioleiomyomatosis (LAM) of the lung, an orphan disease of low-grade malignancy affecting primarily women of childbearing age, are highly associated members of the PEComa family as LAM lung lesions and AML are considered to be different manifestations of the same process. In the lung the LAM cells proliferate to form discrete nodules, which cause cystic destruction of the parenchyma and ultimately respiratory insufficiency. AML/LAM occur sporadically or in patients with tuberous sclerosis complex (TSC) and are etiologically linked to mutations in the TSC1 and TSC2 genes encoding the proteins hamartin (TSC1) and tuberin (TSC2), which are directly involved in suppressing the mechanistic Target Of Rapamycin (mTOR) cell growth signaling pathway. While significant progress has been made in characterizing and pharmacologically slowing the progression of AML/LAM, our understanding of the pathogenesis of AML/LAM lacks an identified cell of origin. Unveiling the specific cell type from which AML/LAM stems is important as it will provide novel treatment options aimed at targeting such a cell’s survival and proliferative capabilities. Here we used an AML derived LAM cell line to determine whether TSC2 restitution brings about the phenotype of the cell from which AML arises. We found that upon TSC2 correction, AML cells exhibited an increase in the expression and number of markers for stem and lymphatic endothelial cell types along with enhanced functional attributes characteristic of these cell lineages. These findings suggested that AML arises from a lymphatic endothelial precursor cell. However some of the abnormal characteristics seen in AML cells remained despite TSC2 correction, suggesting that TSC2 mutations may not be the sole cause of AML/LAM. Furthermore, we demonstrated the effectiveness in repurposing an anti-lymphangiogenic drug as a potential therapeutic option for patients suffering from LAM.