Two distinct epithelial-to-mesenchymal transition programs control invasion and inflammation in segregated tumor cell populations
Epithelial-to-mesenchymal transition (EMT) triggers cell plasticity in embryonic development, adult injured tissues and cancer. Combining the analysis of EMT in cell lines, embryonic neural crest and mouse models of renal fibrosis and breast cancer, we find that there is not a cancer-specific EMT program. Instead, cancer cells dedifferentiate and bifurcate into two distinct and segregated cellular trajectories after activating either embryonic-like or adult-like EMTs to drive dissemination or inflammation, respectively. We show that SNAIL1 acts as a pioneer factor in both EMT trajectories, and PRRX1 drives the progression of the embryonic-like invasive trajectory. We also find that the two trajectories are plastic and interdependent, as the abrogation of the EMT invasive trajectory by deleting Prrx1 not only prevents metastasis but also enhances inflammation, increasing the recruitment of antitumor macrophages. Our data unveil an additional role for EMT in orchestrating intratumor heterogeneity, driving the distribution of functions associated with either inflammation or metastatic dissemination.
Authors
- Cristina López-Blau (ORCID: https://orcid.org/0000-0002-2445-5697)
- M. Ángela Nieto (ORCID: https://orcid.org/0000-0002-3538-840X)
- David Gustavo García-Gutiérrez
- José P. López‐Atalaya (ORCID: https://orcid.org/0000-0001-6064-7584)
- Ángel Márquez-Galera (ORCID: https://orcid.org/0000-0001-8400-9640)
- Gema Moreno‐Bueno (ORCID: https://orcid.org/0000-0002-5030-6687)
- Hassan Fazilaty (ORCID: https://orcid.org/0000-0002-9387-0413)
- Aída Arcas (ORCID: https://orcid.org/0000-0001-9182-0810)
- Nitin Narwade (ORCID: https://orcid.org/0000-0002-1368-307X)
- Khalil Kass Youssef (ORCID: https://orcid.org/0000-0002-4572-3160)
- Joan Galcerán (ORCID: https://orcid.org/0000-0002-5247-2726)
- Amparo Cano
- Raúl Jiménez-Castaño
Institutions
- University of Zurich (CH)
- Instituto de Salud Carlos III (ES)
- Instituto de Neurociencias (ES)
- Instituto de Investigaciones Biomédicas Sols-Morreale (ES)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- MD Anderson Cancer Center Madrid (ES)
- Instituto de Investigación de Enfermedades Raras (ES)
- Universidad Autónoma de Madrid (ES)
- Universidad de Navarra (ES)
Publication Details
- Journal
- Nature Cancer
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1038/s43018-024-00839-5
- Citations
- 66
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 18.65