The methionine cycle sustains the mesenchymal phenotype of tumor cells and drives PDA progression
- 1INSERMU1068, CRCM
Abstract
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.
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BibTeX
@misc{vasseur2026methionine,
title = {{The methionine cycle sustains the mesenchymal phenotype of tumor cells and drives PDA progression}},
author = {S. Vasseur and F. Guillaumond and M. Elodie and Q. Da-Costa and P. Finetti and F. Bertucci and R. Tomasini and N. J. Dusetti and E. Mamessier and G. Efthymiou and E. Jaune-Pons and V. Gouirand and S. S. Tubiana and C. Neuzillet and E. Lohmann and S. Djefaflia-Beloribi and P. Grenot},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.05.764593},
url = {https://www.biorxiv.org/content/10.64898/2026.11.05.764593v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - The methionine cycle sustains the mesenchymal phenotype of tumor cells and drives PDA progression
AU - S. Vasseur
AU - F. Guillaumond
AU - M. Elodie
AU - Q. Da-Costa
AU - P. Finetti
AU - F. Bertucci
AU - R. Tomasini
AU - N. J. Dusetti
AU - E. Mamessier
AU - G. Efthymiou
AU - E. Jaune-Pons
AU - V. Gouirand
AU - S. S. Tubiana
AU - C. Neuzillet
AU - E. Lohmann
AU - S. Djefaflia-Beloribi
AU - P. Grenot
PY - 2026
DA - 2026/11/05
PB - bioRxiv
DO - 10.64898/2026.11.05.764593
UR - https://www.biorxiv.org/content/10.64898/2026.11.05.764593v1
AB - 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.
ER -