RUNX2 Cooperates With SREBP1 to Rewire Cancer Metabolism and Promote Aggressiveness

Authors

Emanuele Vitale
Mila Gugnoni
Veronica Manicardi
Silvia Muccioli
Federica Torricelli
Benedetta Donati
Simonetta Piana
Gloria Manzotti
Elisa Salviato
Francesca Reggiani
Cristian Ascione
Rebecca Vezzani
Moira Ragazzi
Mattia Forcato
Oriana Romano
Silvio Bicciato
Aaron Goldman
Marco Tigano, Thomas Jefferson UniversityFollow
Alessia Ciarrocchi

Document Type

Article

Publication Date

10-31-2025

Comments

This article is the author’s final published version in Journal of Experimental and Clinical Cancer Research, Volume 44, Issue 1, 2025, Article number 298.

The published version is available at https://doi.org/10.1186/s13046-025-03549-7. Copyright © The Author(s) 2025.

Abstract

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.

Recommended Citation

Vitale, Emanuele; Gugnoni, Mila; Manicardi, Veronica; Muccioli, Silvia; Torricelli, Federica; Donati, Benedetta; Piana, Simonetta; Manzotti, Gloria; Salviato, Elisa; Reggiani, Francesca; Ascione, Cristian; Vezzani, Rebecca; Ragazzi, Moira; Forcato, Mattia; Romano, Oriana; Bicciato, Silvio; Goldman, Aaron; Tigano, Marco; and Ciarrocchi, Alessia, "RUNX2 Cooperates With SREBP1 to Rewire Cancer Metabolism and Promote Aggressiveness" (2025). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 467.
https://jdc.jefferson.edu/pacbfp/467

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

41174748

Language

English