Two distinct epithelial-to-mesenchymal transition programs control invasion and inflammation in segregated tumor cell populations

Epithelial-to-mesenchymal transition (EMT) is a complex process involved in development, tissue repair, and cancer. While EMT is often viewed as a single program, this study investigates whether distinct EMT trajectories exist to coordinate different biological functions, such as cell migration and inflammation, within tumors.

The researchers performed a comparative analysis of EMT across multiple models, including embryonic neural crest development, renal fibrosis, and breast cancer (MMTV-PyMT mouse model). They utilized single-cell RNA sequencing, trajectory inference (PAGA, RNA velocity), and transcriptional regulatory network analysis (SCENIC) to map the EMT landscape. They further validated these findings using genetic mouse models (Snail1 and Prrx1 conditional knockouts) and human breast cancer tissue samples.

The study reveals that there is no single cancer-specific EMT program. Instead, cancer cells dedifferentiate and bifurcate into two distinct trajectories:

• Embryonic-like EMT: Driven by the transcription factor PRRX1, this trajectory promotes invasion and metastatic dissemination.
• Adult-like EMT: This trajectory is associated with an inflammatory, injury-repair response, characterized by the secretion of cytokines and recruitment of antitumor macrophages.

SNAIL1 acts as a pioneer factor initiating both pathways, but the trajectories diverge as they progress. Importantly, these programs are interdependent; when the invasive trajectory is blocked (e.g., by deleting Prrx1), the inflammatory trajectory is enhanced, effectively converting cold tumors into hot tumors with increased immune cell infiltration.

This work redefines EMT as a multifaceted process rather than a binary switch. By identifying that tumors contain segregated cell populations dedicated to either invasion or inflammation, the study provides a new framework for understanding intratumor heterogeneity. These findings suggest that targeting specific EMT trajectories could prevent metastasis while simultaneously boosting the immune system's ability to fight cancer, offering a potential strategy for pathway-specific anti-EMT therapies.