The extracellular matrix drives guanylate production and protects pancreatic cancer cells from oxaliplatin-induced DNA damage
The excessive production of extracellular matrix (ECM) and the metabolic adaptations in pancreatic ductal adenocarcinoma (PDAC) contribute individually to enhanced chemoresistance, marked tumor progression, and dismal patient survival. However, ECM-driven metabolic alterations that promote chemoresistance in PDAC are so far unexplored. Here, we use in vitro-generated ECM bioscaffolds that recapitulate cell-ECM interactions and induce broad metabolic alterations in PDAC cells. High-throughput integration of multiomics datasets coupled with metabolic tracing showed that the ECM enhances the generation of guanylates in PDAC cells, the accumulation of which alleviates oxaliplatin-induced DNA damage, and boosts PDAC cell proliferation. These events are guided by the guanosine monophosphate (GMP)-producing enzymes inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate synthase (GMPS), the expression of which correlated with that of matrisomal and DNA repair genes in samples from patients with PDAC. We propose that targeting ECM-driven metabolic processes, such as the enhanced IMPDH activity, may be an effective therapeutic approach for patients with PDAC to bypass the negative side effects of direct targeting of the ECM itself.
Authors
- Paraskevi Kousteridou (ORCID: https://orcid.org/0000-0002-8284-034X)
- Heather S. Carr
- Ivan Nemazanyy (ORCID: https://orcid.org/0000-0001-8080-839X)
- Issam Ben‐Sahra (ORCID: https://orcid.org/0000-0001-9333-4162)
- Pierre Bertrand (ORCID: https://orcid.org/0009-0004-6186-2349)
- Christophe Lachaud (ORCID: https://orcid.org/0000-0003-2762-1619)
- Georgios Efthymiou (ORCID: https://orcid.org/0000-0003-0243-1456)
- Fabienne Guillaumond (ORCID: https://orcid.org/0000-0001-7456-7315)
- Richard Tomasini (ORCID: https://orcid.org/0000-0003-0869-0811)
- Julia Braga Pereira (ORCID: https://orcid.org/0000-0002-0777-2631)
- Ghislain Bidaut (ORCID: https://orcid.org/0000-0001-8502-2361)
- E.R.M.A. Lohmann (ORCID: https://orcid.org/0000-0002-3230-8363)
- Sophie Vasseur (ORCID: https://orcid.org/0000-0002-2339-8854)
- Claudio Montenegro (ORCID: https://orcid.org/0000-0003-2089-1608)
- Pascal Finetti (ORCID: https://orcid.org/0000-0002-2674-3123)
- François Bertucci (ORCID: https://orcid.org/0000-0002-0157-0959)
- Coralie Compare
Institutions
- Northwestern University (US)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Universidade Federal de Pernambuco (BR)
- Centre de Recherche en Cancérologie de Marseille (FR)
- Structure fédérative de recherche Necker (FR)
Publication Details
- Journal
- Science Advances
- Published
- 2025-12-12
- DOI
- https://doi.org/10.1126/sciadv.adu2276
- Primary Topic
- Biochemical and Molecular Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Institut National Du Cancer
- National Cancer Institute