Inhibition of lung tumorigenesis by transient reprogramming in cancer cells
Oncogenic transformation and Oct4, Sox2, Klf4 and c-Myc (OSKM)-mediated induction of pluripotency are two independent and incompatible cellular fates. While continuous expression of OSKM can convert normal somatic cells into teratogenic pluripotent cells, it remains speculative what is the impact of transient OSKM expression in cancer cells. Here, we find that OSKM expression limits the growth of transformed lung cells by inducing apoptosis and senescence. We identify Oct4 and Klf4 as the main individual reprogramming factors responsible for this effect. Mechanistically, the induction of cell cycle inhibitor p21 downstream of the reprogramming factors acts as mediator of cell death and senescence. Using a variety of in vivo systems, including allografts, orthotopic transplantation and KRAS-driven lung cancer mouse models, we demonstrate that transient reprogramming by OSKM expression in cancer cells impairs tumor growth and reduces tumor burden. Altogether, our results show that the induction of transient reprogramming in cancer cells is antitumorigenic opening novel potential therapeutic avenues in oncology.
Authors
- Victor Nuñez-Quintela (ORCID: https://orcid.org/0000-0003-4038-7687)
- Valentín Estévez‐Souto (ORCID: https://orcid.org/0000-0003-4724-358X)
- Mary Denholm (ORCID: https://orcid.org/0000-0001-5875-4487)
- Daniel Muñoz‐Espín (ORCID: https://orcid.org/0000-0002-0550-9514)
- Jose‐Ezequiel Martín (ORCID: https://orcid.org/0000-0002-0051-8868)
- Sabela Da Silva‐Álvarez (ORCID: https://orcid.org/0000-0003-2702-8524)
- Pablo Pedrosa (ORCID: https://orcid.org/0000-0003-0362-2334)
- David Macías (ORCID: https://orcid.org/0000-0002-8676-1964)
- Patricia Lado‐Fernández (ORCID: https://orcid.org/0000-0002-3572-0257)
- Jianfeng Ge (ORCID: https://orcid.org/0000-0003-0972-3312)
- Zhenguang Zhang (ORCID: https://orcid.org/0000-0002-8317-3163)
- Manuel Collado (ORCID: https://orcid.org/0000-0002-0330-0880)
- Anna Dyas
- Maria Gomez-Jenkins (ORCID: https://orcid.org/0000-0003-3682-9219)
- Patricia González (ORCID: https://orcid.org/0009-0007-0011-3880)
Institutions
- Universidade de Santiago de Compostela (ES)
- University of Cambridge (GB)
- Cancer Research UK (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Cancer Research UK Cambridge Center (GB)
- Spanish National Cancer Research Centre (ES)
- Centro Nacional de Biotecnología (ES)
- Center for Research in Molecular Medicine and Chronic Diseases (ES)
- Instituto de Investigación Sanitaria de Santiago (ES)
- Servicio Gallego de Salud (ES)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1038/s41419-024-07207-2
- Citations
- 3
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- AstraZeneca
- Cancer Research UK
- Xunta de Galicia
- Medical Research Council
- Agencia Estatal de Investigación