UNDERSTANDING THE ROLE OF APELIN SIGNALING IN NF2-DEFICIENT MENINGIOMA AND SCHWANNOMA CELLULAR MODELS

Lisa Benecchi1,2, Dr. Srirupa Bhattacharyya2, Roberta Beauchamp2, Dr. Vijaya Ramesh2,3

1Eckerd College, Biology Discipline, Natural Sciences Collegium, St. Petersburg, Florida

2Massachusetts General Hospital, Center for Genomic Medicine, Boston, Massachusetts

3Harvard Medical School, Department of Neurology, Boston, Massachusetts

Neurofibromatosis 2 (NF2) is an autosomal dominant inherited disorder caused by mutations in the NF2 tumor suppressor gene leading to loss of the encoded protein merlin. This disorder is characterized by bilateral vestibular schwannomas and meningiomas arising from Schwann and arachnoid cells, respectively. These tumors, which also occur sporadically, can be highly vascularized and do not respond to conventional chemotherapies. Recent transcriptome analysis of NF2-deficient cell lines revealed significantly increased expression of several growth factor genes, including APLN (apelin) compared with NF2-expressing cells. Apelin is a ligand of the G-protein coupled apelin receptor (APJ), and its signaling is mainly involved in cell proliferation and angiogenesis characterized by the formation of new blood vessels. This research aimed to characterize apelin expression and pathway readouts in NF2-deficient cellular models to aid future development of non-invasive drug treatment for patients affected by NF2. Through quantitative RT-PCR, we observed a significant increase of APLN expression in NF2-null meningioma and Schwann cell lines compared with NF2-expressing cells. Additionally, immunoblotting revealed a significant increase in apelin/APJ pathway readouts in NF2-deficient cells. Moreover, stimulation with exogenous apelin triggered further activation of downstream signaling pathway readouts of APJ in NF2-null cells. Importantly, our results also suggested a potential feedback pathway mechanism, as inhibition of mTOR signaling, a major growth regulator downstream of APJ involved in cell proliferation, significantly decreased apelin expression in NF2-null cells. Therefore, apelin could be a potential therapeutic target for NF2.

For more information, email: lbenecc@eckerd.edu

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