Pdk1-dependent metabolic heterogeneity promotes aggressive colorectal cancer through cell-intrinsic interferon signaling
- 1University of Barcelona
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.
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BibTeX
@misc{calviello2026pdk1dependent,
title = {{Pdk1-dependent metabolic heterogeneity promotes aggressive colorectal cancer through cell-intrinsic interferon signaling}},
author = {J. Calviello and L. Poeltl and A. Mira and F. Spini and A. Larranaga and L. Fortuny and F. Vianello and A. Bonilla-Diaz and A. Alvarez-Munoz and G. Pazzagli and M. Serra and N. Ducano and M. Gut and E. Casals and A. Esteve-Codina and M. Liesa and L. Trusolino and A. Sapino and D. Sebastian and C. Sebastian},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.757309},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757309v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Pdk1-dependent metabolic heterogeneity promotes aggressive colorectal cancer through cell-intrinsic interferon signaling
AU - J. Calviello
AU - L. Poeltl
AU - A. Mira
AU - F. Spini
AU - A. Larranaga
AU - L. Fortuny
AU - F. Vianello
AU - A. Bonilla-Diaz
AU - A. Alvarez-Munoz
AU - G. Pazzagli
AU - M. Serra
AU - N. Ducano
AU - M. Gut
AU - E. Casals
AU - A. Esteve-Codina
AU - M. Liesa
AU - L. Trusolino
AU - A. Sapino
AU - D. Sebastian
AU - C. Sebastian
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.757309
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.757309v1
AB - 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.
ER -