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.上皮间质转化（Epithelial-to-mesenchymal transition, EMT）可在胚胎发育、成年受损组织及癌症进程中诱发细胞可塑性。本研究通过整合分析细胞系、胚胎神经嵴、肾纤维化小鼠模型与乳腺癌模型中的EMT相关特征，发现并不存在癌症特异性的EMT程序。与之相反，癌细胞在激活类胚胎型或类成年型EMT后，会发生去分化并分化为两条截然不同且相互隔离的细胞轨迹，分别推动肿瘤转移扩散与炎症反应的发生。研究证实，SNAIL1在两条EMT轨迹中均充当先锋因子（pioneer factor），而PRRX1则驱动类胚胎型侵袭性轨迹的进展。此外本研究还发现，两条轨迹兼具可塑性与相互依存性：通过敲除Prrx1以阻断EMT侵袭性轨迹，不仅能够抑制肿瘤转移，还可增强炎症反应，促进抗肿瘤巨噬细胞的招募。本研究数据揭示了EMT在调控肿瘤内异质性方面的额外作用，即驱动与炎症或转移性扩散相关的功能分布。