Work

Pdk1-dependent metabolic heterogeneity promotes aggressive colorectal cancer through cell-intrinsic interferon signaling

Year: 2026

Type: preprint

Abstract: Tumor heterogeneity is a major determinant of tumor progression and therapeutic resistance, yet the contribution of metabolism to intratumoral heterogeneity still remains poorly explored. Here, we find that pyruvate dehydrogenase kinase-1 (Pdk1) expression defines metabolically distinct cancer cell populations in colorectal tumors. Image-based spatial single-cell phenotyping shows that Pdk1 high cells are associated with tumor progression in orthotopic models of colorectal cancer (CRC). Genetic ablation experiments demonstrate the role of Pdk1 high cells in tumor growth, 5-fluorouracil chemoresistance and tumor relapse. Mechanistically, we identify a link between Pdk1-driven metabolic states and specific cell phenotypes, where Pdk1 high cancer cells exhibit an EMT, stem cell-like phenotype characterized by increased interferon (IFN) signaling. Mitochondrial remodeling in Pdk1 high cells leads to the release of mitochondrial DNA to the cytosol and activation of IFN pathways, promoting Pdk1-driven phenotypes. Inhibition of IFN signaling impairs the tumorigenic and aggressive features of Pdk1 high cancer cells, thus establishing a functional connection between metabolic heterogeneity, cell-intrinsic IFN signaling and aggressive CRC.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.07.757309