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• Olschewski A
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The RESPImmun Faculty

	Gerald HÖFLER, MD LipONCO: Interaction of adipose triglyceride lipase (ATGL) with lung cancer-inducing gene mutations
Diagnostic and Research Center for Molecular Medicine, Diagnostic and Research Institute for Pathology; Medical University of Graz, Neue Stiftingtalstraße 5, A-8010 Graz; phone: +43-316-385 71737, fax: +43-316-385 79001, ✉ e-mail
websites: [RESPImmun] [DK-MCD] [MUG¹] [MUG²]
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Gerald Höfler is a clinical pathologist specialized in molecular and haemato-pathology. His expertise provides the opportunity to combine clinically important observations and pathohistological analyses with basic research. He stablished the role of adipose triglyceride lipase (ATGL) in cancer cachexia and cancer development. Currently, his research focuses on the role of metabolic lipases in lung cancer initiation and progression with a special emphasis on a potential role of inflammation in the pathogenesis of lung cancer. Within the program, he will work closely with Katharina Leithner, Julia Kargl and Horst Olschewski. He is coordinator of the DK-MCD.

Project

Project 11: LipoIMMUNE, Impact of monoglyceride lipase on the tumor microenvironment
Co-PI: Paul Vesely

Background

Monoglyceride lipase (MGL) is the rate-limiting enzyme for monoglyceride (MG) hydrolysis. 2-arachidonylglycerol (2-AG), one of the most prominent MGs, acts as an endocannabinoid receptor (CBR) agonist, systemically inhibiting pain and inflammation. MGL however, hydrolyzes 2-AG yielding glycerol and arachidonic acid (AA). Thereby, MGL limits the anti-inflammatory capacity of the endocannabinoid (EC)-system and, at the same time, provides AA, the precursor for eicosanoid inflammation mediators. In mice, systemic knockout (KO) of MGL increases the incidence of lung adenocarcinoma. Similarly, MGL deficiency impairs anti tumorigenic functions of the tumor microenvironment (TME): CBR-2 dependent activation of tumor associated macrophages (TAMs) promotes tumor growth through suppression of tumor cell toxic CD8+ T cells. Conversely, in tumor cells MGL promotes a fatty acid network of signaling lipids. These include, lysophospholipids, ether lipids, phosphatidic acid and prostaglandin E₂, favoring cell migration, invasion, survival, and tumor growth. Focusing on lipolytic enzymes in cancer biology, we observed that tumor cell-specific MGL KO reduced lung tumor load and density of TAM infiltrates.

Hypothesis and objectives

MGL shows context dependent pro- or anti-cancerogenic activities. It promotes oncogenic lipid signaling in tumor cells and at the same time regulates the immune response via the EC system and AA metabolites, i. e. eicosanoids. We therefore, hypothesize that MGL shows tumor-promoting or -suppressive functions through its interaction with the TME.

Methodology

The conditional pRb/p53 knockout (Rbp53) and conditional KRASG12D (LSL-KRAS) lung cancer models will be applied as LSL-KRAS show substantially denser TAM infiltrates than Rbp53. These models should enable to understand if the extremely diverse roles of MGL in cancer biology can be explained by tumor specific TME. The prospective PhD student will (i) establish Rbp53 and LSL-KRAS mouse lines with conditional or complete lack of MGL, (ii) analyze tumors and TMEs of each tumor model, (iii) perform mechanistical studies to understand interaction of tumor cells and their TME. In year 1, the PhD student will establish experimental cancer models. An MGL-ko line and a conditional MGL-ko (MGL-flox) line are crossbred with either Rbp53 or LSL-KRAS mice. The resultant lines will allow to test the impact of tumor cell specific or systemic MGL-ko in the two different tumor models. In year 2 – 3, the student will induce experimental lung cancer through inhalation of CRE expressing adenoviruses in each of the established lines. Additionally, diverse patient derived lung cancer samples will be acquired. Lung tumors and TME will be assessed by immunohistochemistry and by flow cytometry analyses. The student will also applied standard techniques including qRT-PCR, in situ RNA hybridization, western immunoblotting and lipase activity measurements with ¹⁴C-labeled lipid substrates. Mass spectrometric lipid analyses will be performed at the lipid core of the Medical University of Graz (Med Uni Graz). Cytokine and chemokine analyses will be performed using ELISA assays and, using the Bio-Plex 200 at the Med Uni Graz cytometric flow core. In year 3 – 4, the student will test if pharmacological interventions in MGL metabolism can ameliorate tumor growth and aggressiveness.

Input from collaborations within the RESPImmun programme

Hotst Olschewski will provide patient-derived BAL samples,
Julia Kargl and Katharina Leithner will train the student in fluorescence-aided cell sorting techniques and collaborate with us assessing the immunological TME and its interactions with the tumor cells.
Leigh Marsh will support the project with his immune cell expertise.