B10 - Molecular causes for lipomatosis associated with hyperactivation of the PTEN/PI3K/AKT/mTOR pathway
Severe lipomatosis or adipose tissue overgrowth frequently occurs in children and adolescents with germline mutations in PTEN (phosphatase and tensin homolog), which encodes a major negative regulator of PI3 kinase growth factor signalling. In order to analyse molecular causes of lipoma formation associated with defects in PTEN, we will use a lipoma animal model with conditional Pten knockout in osteo-chondroprogenitor cells (collaboration with N. Klöting). In addition to the in vivo model, we will establish suitable cell models by downregulating PTEN or overexpressing a constitutively active PI3 kinase in adipose-derived mesenchymal stem cells.
We anticipate relevant dysregulations in signalling pathways, which link to adipogenesis and proliferation of (pre)adipocytes/lipoma cells. Target-specific pharmaceuticals will be tested that could reverse pathological adipogenesis and adipose tissue overgrowth. A better understanding of this prototypic monogenic orphan disease will not only provide treatment options for the affected patients but also inform on basic mechanisms of adipocyte differentiation and proliferation and add to the functional and molecular understanding of the pathogenesis of obesity.
Figure: 1A: Schematic overview of the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway which is constitutively active under conditions of phosphatase and tensin homolog (PTEN) haploinsufficiency caused by PTEN germline mutations. 1B: Adipose tissue sections from a lipoma of a patient with PTEN mutation (left) and age-matched control (right). Scale bar = 100 µm 1C: Quantification of adipocyte size in adipose tissue sections of patients with PTEN or PI3K mutations and age-matched controls.
Kässner F, Kirstein A, Händel N, Schmid GL, Landgraf K, Berthold A, Tannert A, Schaefer M, Wabitsch M, Kiess W, Körner A, Garten A. A New Human Adipocyte Model With PTEN Haploinsufficiency. Adipocyte. 2020 Dec;9(1):290-301.
Le Duc D, Lin CC, Popkova Y, Yang Z, Akhil V, Çakir MV, Grunewald S, Simon JC, Dietz A, Dannenberger D, Garten A, Lemke JR, Schiller J, Blüher M, Nono Nankam PA, Rolle-Kampczyk U, von Bergen M, Kelso J, Schöneberg T. Reduced lipolysis in lipoma phenocopies lipid accumulation in obesity. Int J Obes (Lond). 2020 Nov 24.
Kirstein A, Augustin A, Penke M, Cea M, Körner A, Kies W, Garten A.The Novel Phosphatidylinositol-3-Kinase (PI3K) Inhibitor Alpelisib Effectively Inhibits Growth of PTEN-Haploinsufficient Lipoma Cells. Cancers (Basel). 2019 Oct 17;11(10)
Buhl JP, Garten A, Kratzsch J, Kiess W, Penke M. How Reliable are Commercially Available Glypican4 ELISA Kits? Exp Clin Endocrinol Diabetes. 2020 Oct 16.
Bohn C, Vogel M, Spielau U, Hilbert C, Kiess W, Körner A. Birth weight increases with birth order despite decreasing maternal pregnancy weight gain. Acta Paediatrica 2020 Sept.
Garten A, Grohmann T, Kluckova K, Lavery GG, Kiess W, Penke M. Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1. Int J Mol Sci. 2019 Aug 19;20(16). pii: E4048.
Sociali G, Grozio A, Caffa I, Schuster S, Becherini P, Damonte P, Sturla L, Fresia C, Passalacqua M, Mazzola F, Raffaelli N, Garten A, Kiess W, Cea M, Nencioni A, Bruzzone S. SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells. FASEB J. 2018 Dec 4:fj201800321R.
Grohmann T, Penke M, Petzold-Quinque S, Schuster S, Richter S, Kiess W, Garten A. Inhibition of NAMPT sensitizes MOLT4 leukemia cells for etoposide treatment through the SIRT2-p53 pathway. Leukemia Res. 2018 Jun,69, 39–46.
Kässner F, Sauer T, Penke M, Richter S, Landgraf K, Körner A, Kiess W, Händel N, Garten A.Simvastatin induces apoptosis in PTEN‑haploinsufficient lipoma cells. Int J Mol Med. 2018 Mar 14.
Penke M, Schuster S, Gorski T, Gebhardt R, Kiess W, Garten A. Oleate ameliorates palmite-induced reduction of NAMPT activity and NAD levels in primary human hepatocytes and hepatocarcinoma cells. Lipids Health Dis. 2017;16:191.
Leipert J, Kässner F, Schuster S, Händel N, Körner A, Kiess W, Garten A. Resveratrol potentiates growth inhibitory effects of rapamycin in PTEN-deficient lipoma cells by suppressing p70S6 kinase activity. Nutr Cancer. 2016;68:342-9.
Wilhelm F, Kässner F, Schmid G, Kratzsch J, Laner A, Wabitsch M, Körner A, Kiess W, Garten A. Phosphatidylinositol 3-kinase (PI3K) signalling regulates insulin-like-growth factor binding protein-2 (IGFBP-2) production in human adipocytes. Growth Horm IGF Res. 2015;25:115-20.
Schmid GL, Kässner F, Uhlig HH, Körner A, Kratzsch J, Händel N, Zepp FP, Kowalzik F, Laner A, Starke S, Wilhelm FK, Schuster S, Viehweger A, Hirsch W, Kiess W, Garten A. Sirolimus treatment of severe PTEN hamartoma tumor syndrome: case report and in vitro studies. Pediatr Res. 2014;75:527-34.