Honeder, Sophie Elisabeth

Liesinger, Laura

Hadrbolec, Matthias

Mayr, Moritz

Pirchheim, Anita

Prem, Dominik

Gindlhuber, Juergen

Brcic, Luka

Lindenmann, Joerg

Haemmerle, Guenter

Kratky, Dagmar

Schittmayer-Schantl, Matthias

Tomin, Tamara

Birner-Grünberger, Ruth

2025-10-02T08:14:20Z

2025-10-02T08:14:20Z

2025-09-13

<div class="csl-bib-body"> <div class="csl-entry">Honeder, S. E., Liesinger, L., Hadrbolec, M., Mayr, M., Pirchheim, A., Prem, D., Gindlhuber, J., Brcic, L., Lindenmann, J., Haemmerle, G., Kratky, D., Schittmayer-Schantl, M., Tomin, T., &#38; Birner-Grünberger, R. (2025, September 13). <i>Lipid Hydrolase Downregulation Shapes the Lipid Landscape in Non-Small Cell Lung Cancer</i> [Conference Presentation]. APMRS 2025, Wien, Austria. http://hdl.handle.net/20.500.12708/219596</div> </div>

http://hdl.handle.net/20.500.12708/219596

Alterations in lipid metabolism are a hallmark of cancer, with increased lipogenesis, fatty acid (FA) uptake, and lipid droplet accumulation emerging as defining features of many solid tumors. However, the role of lipid hydrolysis in cancer metabolism remains underexplored. To address this, we employed unbiased serine hydrolase-directed activity-based protein profiling of patient-derived lung tumors and adjacent normal tissue, combined with comprehensive proteomics and lipidomics analysis. Strikingly, several lipid hydrolases showed reduced activity and abundance in lung tumors, including monoglyceride lipase (MGL), epoxide hydrolase 1 (EPHX1), carboxylesterase 1 (CES1), neutral cholesterol ester hydrolase 1 (NCEH1), and patatin-like phospholipase domain-containing protein 6 (PNPLA6). Concomitantly, the lipid profile of tumors was altered, with many lipid species elevated. Triacylglycerols were especially enriched in tumors, particularly those containing long-chain and highly unsaturated FAs, suggesting lipid droplet accumulation. This was further supported by increased levels of the lipid droplet scaffolding protein Perilipin-2 (PLIN2), while ATGL - the main triacylglycerol hydrolase - was reduced in tumors, as confirmed by immunofluorescent staining. Lipid substrate assays of the downregulated hydrolases revealed that most possess monoacylglycerol (MG) hydrolysis activity, among others. Consistent with this, several MG species and the overall lipid class were more abundant in tumors, corroborating decreased monoacylglycerol hydrolysis in lung tumors. To investigate the functional consequences of reduced lipid hydrolase expression, we generated NSCLC cell lines stably overexpressing ATGL, MGL, EPHX1, CES1, NCEH1, or PNPLA6. Overexpression led to significantly reduced proliferation and extensive lipid remodeling, as shown by lipidomics analysis. This remodeling likely reflects cellular compensation for excess free FAs released upon heightened lipid hydrolysis, which must be re-esterified to prevent lipotoxic stress. In several cases, overexpression also reactivated FA β-oxidation, a pathway suppressed in tumors. Together, our findings indicate that reduced lipid hydrolase activity is a hallmark of NSCLC, contributing to a reprogrammed lipid metabolism geared toward storage rather than catabolism. This shift may help tumors mitigate oxidative stress and promote growth, while the restoration of lipid hydrolysis presents a potential metabolic vulnerability.

FWF - Österr. Wissenschaftsfonds

en

lipid metabolism

lung cancer

lipid hydrolases

Lipid Hydrolase Downregulation Shapes the Lipid Landscape in Non-Small Cell Lung Cancer

Presentation

Vortrag

TU Wien

Medical University of Graz, Austria

Institute of Molecular Biosciences - University of Graz (Graz, AT)

Cardiology - Medical University of Graz (Graz, AT)

Department of Pathology - Medical University of Vienna (Vienna, AT)

Medical University of Graz, Austria

University of Graz, Austria

Gottfried Schatz Research Center - Medical University of Graz (Graz, AT)

F 7309-B21

Conference Presentation

Lipidhydrolyse im Krebs und in Lipid-assoziierten Krankheiten

Cell Culture Core Facility (CCCF)

X1

Beyond TUW-research focus

100

E164-01-3 - Forschungsgruppe Bioanalytik

0009-0004-6992-5770

0000-0002-6155-5208

0000-0002-9098-8416

0000-0003-1276-7666

0000-0003-1357-7573

0000-0003-3249-655X

0000-0002-7071-2316

0000-0003-3950-0312

APMRS 2025

12-09-2025

13-09-2025

On Site

Event for scientific audience

Wien

AT

APMA, TU Wien

Honeder, Sophie Elisabeth

Single Track

Chemie

Biologie

Anatomie, Pathologie, Physiologie

1040

1060

3011

50

30

20

en

none

conference paper not in proceedings

http://purl.org/coar/resource_type/c_18cp

Publications

no Fulltext

FWF - Österr. Wissenschaftsfonds

F 7309-B21

E164-01-3 - Forschungsgruppe Bioanalytik

E164-01-3 - Forschungsgruppe Bioanalytik

E164-01-3 - Forschungsgruppe Bioanalytik

TU Wien

Medical University of Graz, Austria

Institute of Molecular Biosciences - University of Graz (Graz, AT)

Cardiology - Medical University of Graz (Graz, AT)

Department of Pathology - Medical University of Vienna (Vienna, AT)

Gottfried Schatz Research Center - Medical University of Graz (Graz, AT)

E164-01-3 - Forschungsgruppe Bioanalytik

E164-01-3 - Forschungsgruppe Bioanalytik

E164-01 - Forschungsbereich Imaging und Instrumentelle Analytische Chemie

0009-0004-6992-5770

0000-0002-6155-5208

0000-0002-9098-8416

0000-0003-1276-7666

0000-0003-1357-7573

0000-0003-3249-655X

0000-0002-7071-2316

0000-0003-3950-0312

E164-01 - Forschungsbereich Imaging und Instrumentelle Analytische Chemie

E164-01 - Forschungsbereich Imaging und Instrumentelle Analytische Chemie

E164-01 - Forschungsbereich Imaging und Instrumentelle Analytische Chemie

E164-01 - Forschungsbereich Imaging und Instrumentelle Analytische Chemie

E164-01 - Forschungsbereich Imaging und Instrumentelle Analytische Chemie

E164 - Institut für Chemische Technologien und Analytik