RUNX2 cooperates with SREBP1 to rewire cancer metabolism and promote aggressiveness
Embryonic Transcription Factors (TFs) are often reactivated in cancer, driving developmental gene programs that support phenotypic plasticity. Metabolic adaptation fuels this plasticity by supplying energy and molecular building blocks for growth. RUNX2, the master regulator of bone morphogenesis, is ectopically expressed in epithelial cancer, promoting metastasis through trans-differentiation processes like Epithelial-to-Mesenchymal Transition (EMT) and osteomimicry. By combining omics data with functional validation, we demonstrated that RUNX2 drives cancer cell metabolic rewiring by repressing mitochondrial respiration while promoting anabolic processes. We showed that RUNX2 upregulates key genes of lipid biosynthesis by regulating and cooperating with SREBP1. In vivo expression analysis in thyroid and breast cancer patients confirmed that lipid metabolism and SREBF1 expression are associated with increased metastatic potential and clinical aggressiveness. These findings emphasize the RUNX2 role in cancer plasticity and indicate metabolic adaptation as an integral part of the trans-differentiation program induced by this TF during cancer progression.
Authors
- Elisa Salviato (ORCID: https://orcid.org/0000-0003-3246-7820)
- Gloria Manzotti (ORCID: https://orcid.org/0000-0002-0639-3605)
- Veronica Manicardi (ORCID: https://orcid.org/0000-0003-2490-7283)
- Alessia Ciarrocchi (ORCID: https://orcid.org/0000-0002-5541-2075)
- Benedetta Donati (ORCID: https://orcid.org/0000-0002-9163-8194)
- Silvia Muccioli (ORCID: https://orcid.org/0000-0002-0544-6808)
- Francesca Reggiani (ORCID: https://orcid.org/0000-0002-4090-8908)
- Mattia Forcato (ORCID: https://orcid.org/0000-0002-7383-6576)
- Oriana Romano (ORCID: https://orcid.org/0000-0002-3483-1115)
- Federica Torricelli (ORCID: https://orcid.org/0000-0003-1954-5695)
- Simonetta Piana (ORCID: https://orcid.org/0000-0003-4875-6977)
- Aaron R. Goldman (ORCID: https://orcid.org/0000-0001-7605-9592)
- Silvio Bicciato (ORCID: https://orcid.org/0000-0002-1944-7078)
- Mila Gugnoni (ORCID: https://orcid.org/0000-0003-4630-3958)
- Marco Tigano (ORCID: https://orcid.org/0000-0002-4353-9220)
- Moira Ragazzi (ORCID: https://orcid.org/0000-0002-8761-9265)
- Cristian Ascione (ORCID: https://orcid.org/0009-0007-3297-0262)
- Emanuele Vitale (ORCID: https://orcid.org/0000-0003-1866-2101)
- Rebecca Vezzani
Institutions
- The Wistar Institute (US)
- University of Modena and Reggio Emilia (IT)
- University of Padua (IT)
- Thomas Jefferson University (US)
- Azienda Sanitaria Unità Locale di Reggio Emilia (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
Publication Details
- Journal
- Journal of Experimental & Clinical Cancer Research
- Published
- 2025-10-31
- DOI
- https://doi.org/10.1186/s13046-025-03549-7
- Citations
- 2
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.87