PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma
Abstract Anti-epidermal growth factor receptor (EGFR) therapy (cetuximab) shows a limited clinical benefit for patients with locally advanced or recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), due to the frequent occurrence of secondary resistance mechanisms. Here we report that...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56675-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832571545428426752 |
|---|---|
| author | Valentin Van den bossche Julie Vignau Engy Vigneron Isabella Rizzi Hannah Zaryouh An Wouters Jérôme Ambroise Steven Van Laere Simon Beyaert Raphaël Helaers Cédric van Marcke Lionel Mignion Elise Y. Lepicard Bénédicte F. Jordan Céline Guilbaud Olivier Lowyck Hajar Dahou Antonella Mendola Manon Desgres Léo Aubert Isabelle Gerin Guido T. Bommer Romain Boidot Perrine Vermonden Aurélien Warnant Yvan Larondelle Jean-Pascal Machiels Olivier Feron Sandra Schmitz Cyril Corbet |
| author_facet | Valentin Van den bossche Julie Vignau Engy Vigneron Isabella Rizzi Hannah Zaryouh An Wouters Jérôme Ambroise Steven Van Laere Simon Beyaert Raphaël Helaers Cédric van Marcke Lionel Mignion Elise Y. Lepicard Bénédicte F. Jordan Céline Guilbaud Olivier Lowyck Hajar Dahou Antonella Mendola Manon Desgres Léo Aubert Isabelle Gerin Guido T. Bommer Romain Boidot Perrine Vermonden Aurélien Warnant Yvan Larondelle Jean-Pascal Machiels Olivier Feron Sandra Schmitz Cyril Corbet |
| author_sort | Valentin Van den bossche |
| collection | DOAJ |
| description | Abstract Anti-epidermal growth factor receptor (EGFR) therapy (cetuximab) shows a limited clinical benefit for patients with locally advanced or recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), due to the frequent occurrence of secondary resistance mechanisms. Here we report that cetuximab-resistant HNSCC cells display a peroxisome proliferator-activated receptor alpha (PPARα)-mediated lipid metabolism reprogramming, with increased fatty acid uptake and oxidation capacities, while glycolysis is not modified. This metabolic shift makes cetuximab-resistant HNSCC cells particularly sensitive to a pharmacological inhibition of either carnitine palmitoyltransferase 1A (CPT1A) or PPARα in 3D spheroids and tumor xenografts in mice. Importantly, the PPARα-related gene signature, in human clinical datasets, correlates with lower response to anti-EGFR therapy and poor survival in HNSCC patients, thereby validating its clinical relevance. This study points out lipid metabolism rewiring as a non-genetic resistance-causing mechanism in HNSCC that may be therapeutically targeted to overcome acquired resistance to anti-EGFR therapy. |
| format | Article |
| id | doaj-art-cbc870bfa49844399054114b81a5a097 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-cbc870bfa49844399054114b81a5a0972025-02-02T12:33:12ZengNature PortfolioNature Communications2041-17232025-02-0116112110.1038/s41467-025-56675-3PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinomaValentin Van den bossche0Julie Vignau1Engy Vigneron2Isabella Rizzi3Hannah Zaryouh4An Wouters5Jérôme Ambroise6Steven Van Laere7Simon Beyaert8Raphaël Helaers9Cédric van Marcke10Lionel Mignion11Elise Y. Lepicard12Bénédicte F. Jordan13Céline Guilbaud14Olivier Lowyck15Hajar Dahou16Antonella Mendola17Manon Desgres18Léo Aubert19Isabelle Gerin20Guido T. Bommer21Romain Boidot22Perrine Vermonden23Aurélien Warnant24Yvan Larondelle25Jean-Pascal Machiels26Olivier Feron27Sandra Schmitz28Cyril Corbet29Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvainPole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvainPole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvainPole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvainCenter for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of AntwerpCenter for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of AntwerpCentre des Technologies Moléculaires Appliquées (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvainTranslational Cancer Research Unit (TCRU), GZA ZiekenhuizenKing Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-LucLaboratory of Human Molecular Genetics, de Duve Institute, UCLouvainKing Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-LucBiomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvainBiomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvainBiomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvainPole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvainKing Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-LucPole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvainPole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvainPole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvainPole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvainMetabolic Research Group, de Duve Institute, UCLouvainMetabolic Research Group, de Duve Institute, UCLouvainUnit of Molecular Biology, Department of Biology and Pathology of Tumors, Georges‑François Leclerc Cancer Center‑UNICANCERLouvain Institute of Biomolecular Science and Technology (LIBST), UCLouvainLouvain Institute of Biomolecular Science and Technology (LIBST), UCLouvainLouvain Institute of Biomolecular Science and Technology (LIBST), UCLouvainKing Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-LucPole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvainKing Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-LucPole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvainAbstract Anti-epidermal growth factor receptor (EGFR) therapy (cetuximab) shows a limited clinical benefit for patients with locally advanced or recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), due to the frequent occurrence of secondary resistance mechanisms. Here we report that cetuximab-resistant HNSCC cells display a peroxisome proliferator-activated receptor alpha (PPARα)-mediated lipid metabolism reprogramming, with increased fatty acid uptake and oxidation capacities, while glycolysis is not modified. This metabolic shift makes cetuximab-resistant HNSCC cells particularly sensitive to a pharmacological inhibition of either carnitine palmitoyltransferase 1A (CPT1A) or PPARα in 3D spheroids and tumor xenografts in mice. Importantly, the PPARα-related gene signature, in human clinical datasets, correlates with lower response to anti-EGFR therapy and poor survival in HNSCC patients, thereby validating its clinical relevance. This study points out lipid metabolism rewiring as a non-genetic resistance-causing mechanism in HNSCC that may be therapeutically targeted to overcome acquired resistance to anti-EGFR therapy.https://doi.org/10.1038/s41467-025-56675-3 |
| spellingShingle | Valentin Van den bossche Julie Vignau Engy Vigneron Isabella Rizzi Hannah Zaryouh An Wouters Jérôme Ambroise Steven Van Laere Simon Beyaert Raphaël Helaers Cédric van Marcke Lionel Mignion Elise Y. Lepicard Bénédicte F. Jordan Céline Guilbaud Olivier Lowyck Hajar Dahou Antonella Mendola Manon Desgres Léo Aubert Isabelle Gerin Guido T. Bommer Romain Boidot Perrine Vermonden Aurélien Warnant Yvan Larondelle Jean-Pascal Machiels Olivier Feron Sandra Schmitz Cyril Corbet PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma Nature Communications |
| title | PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma |
| title_full | PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma |
| title_fullStr | PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma |
| title_full_unstemmed | PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma |
| title_short | PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma |
| title_sort | pparα mediated lipid metabolism reprogramming supports anti egfr therapy resistance in head and neck squamous cell carcinoma |
| url | https://doi.org/10.1038/s41467-025-56675-3 |
| work_keys_str_mv | AT valentinvandenbossche pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT julievignau pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT engyvigneron pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT isabellarizzi pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT hannahzaryouh pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT anwouters pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT jeromeambroise pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT stevenvanlaere pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT simonbeyaert pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT raphaelhelaers pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT cedricvanmarcke pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT lionelmignion pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT eliseylepicard pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT benedictefjordan pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT celineguilbaud pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT olivierlowyck pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT hajardahou pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT antonellamendola pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT manondesgres pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT leoaubert pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT isabellegerin pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT guidotbommer pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT romainboidot pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT perrinevermonden pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT aurelienwarnant pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT yvanlarondelle pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT jeanpascalmachiels pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT olivierferon pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT sandraschmitz pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma AT cyrilcorbet pparamediatedlipidmetabolismreprogrammingsupportsantiegfrtherapyresistanceinheadandnecksquamouscellcarcinoma |