The methionine cycle sustains the mesenchymal phenotype of tumor cells and drives PDA progression
Mesenchymal traits are associated with poor prognosis in Pancreatic Ductal Adenocarcinoma (PDA), but direct targeting of mesenchymal tumor cells remains a challenge. Metabolic profiling of tumor cells isolated from murine PDA and liver metastases (LM) revealed that LM rely more on the methionine cycle than does primary PDA. This metabolic shift was specifically associated with increased activation of the methionine cycle in mesenchymal tumor cells compared to differentiated tumor cells. We show that the targeting of the key enzyme of the methionine cycle S-adenosylhomocysteine hydrolase (SAHH) in mesenchymal cells lowers the levels of homocysteine (Hcy) and glutathione, resulting in reduced antioxidant capacity, deregulated intracellular calcium homeostasis, and ultimately loss of mesenchymal markers. Together, these events decrease cell proliferation and invasion, blunting the tumorigenic and metastatic potential of SAHH-deficient cells, eventually impeding tumor growth and progression of the metastatic disease. Clinically, the high expression of SAHH in patients with mesenchymal PDA is correlated with poor survival, positioning SAHH as a potential therapeutic target to impede the pro-metastatic, mesenchymal phenotype of PDA.
Authors
- Nelson Dusetti (ORCID: https://orcid.org/0000-0002-6161-8483)
- Eugénie Lohmann
- Cindy Neuzillet (ORCID: https://orcid.org/0000-0001-7037-7477)
- Pierre Grenot (ORCID: https://orcid.org/0000-0003-3991-753X)
- Georgios Efthymiou (ORCID: https://orcid.org/0000-0003-0243-1456)
- Fabienne Guillaumond (ORCID: https://orcid.org/0000-0001-7456-7315)
- Émilie Mamessier (ORCID: https://orcid.org/0000-0002-3516-0093)
- Richard Tomasini (ORCID: https://orcid.org/0000-0003-0869-0811)
- Quentin Da Costa (ORCID: https://orcid.org/0000-0001-8904-9131)
- Victoire Gouirand (ORCID: https://orcid.org/0000-0002-2666-0061)
- Sophie Vasseur (ORCID: https://orcid.org/0000-0002-2339-8854)
- Pascal Finetti (ORCID: https://orcid.org/0000-0002-2674-3123)
- Emilie Jaune (ORCID: https://orcid.org/0000-0002-5787-0803)
- François Bertucci (ORCID: https://orcid.org/0000-0002-0157-0959)
- Metay Elodie
- Sadia Djefaflia-Beloribi
- Sarah Simba Tubiana
Institutions
- Inserm (FR)
- Calmette Hospital (KH)
- Centre de Recherche en Cancérologie de Marseille (FR)
- Institut Paoli-Calmettes (FR)
- Centre d'Immunophénomique (FR)
- Institut Curie (FR)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-11-07
- DOI
- https://doi.org/10.64898/2026.11.05.764593
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- preprint
Funders
- Association pour la Recherche sur le Cancer
- Fondation pour la Recherche Médicale
- Ligue Contre le Cancer
- Fondation de France
- Institut National Du Cancer