Mediator subunit MED4 enforces metastatic dormancy in breast cancer
Menée à l'aide de lignées cellulaires, de modèles murins et d'une technique de criblage génétique à l'échelle du génome, cette étude met en évidence un mécanisme par lequel la sous-unité 4 du complexe médiateur de la transcription de l'ARN polymérase II (MED4) induit la dormance métastatique, démontre qu'une haplo-insuffisance de MED4 favorise à terme le développement de métastases via le remodelage de la matrice extracellulaire et la mise en oeuvre de programmes de mécanotransduction puis révèle une association entre l'haplo-insuffisance de MED4 et le pronostic
Long-term survival in breast cancer is often limited by metastatic recurrence arising from disseminated cancer cells that persist in a dormant state. The mechanisms that enable these dormant cells to survive and subsequently reawaken remain incompletely understood. Here an unbiased genome-scale genetic screen identified Med4 as a cancer cell-intrinsic gatekeeper in metastatic reactivation. Correspondingly, MED4 haploinsufficiency was found to be prevalent in metastatic breast cancer and associated with poorer clinical outcomes. Syngeneic mouse metastasis models revealed that MED4 enforces metastatic dormancy. Mechanistically, and unexpectedly given the canonical role of the Mediator complex in transcriptional activation, MED4 suppresses enhancer priming (H3K4me1) and activation (H3K27ac). Loss of a single Med4 allele disrupts enhancer poise, leading to extracellular matrix remodelling and integrin-mediated mechanotransduction programmes that ultimately drive metastatic outgrowth. Together, these findings establish MED4 as a key regulator of breast cancer cell dormancy and nominate MED4 haploinsufficiency as a potential predictive biomarker for patients at high risk of metastatic relapse.
Nature Cell Biology , article en libre accès, 2026