Multi-organ Site Metastatic Reactivation Mediated by Non-canonical Discoidin Domain Receptor 1 Signaling
Menée in vitro et in vivo sur des modèles de cancer du sein, cette étude met en évidence des mécanismes par lesquels la tétraspanine TM4SF1 favorise la réactivation du processus métastatique dans le poumon, les os et le cerveau
Genetic screening identifies the atypical tetraspanin TM4SF1 as a strong mediator of metastatic reactivation of breast cancer. Intriguingly, TM4SF1 couples the collagen receptor tyrosine kinase DDR1 to the cortical adaptor syntenin 2 and, hence, to PKCα. The latter kinase phosphorylates and activates JAK2, leading to the activation of STAT3. This non-canonical mechanism of signaling induces the expression of SOX2 and NANOG; sustains the manifestation of cancer stem cell traits; and drives metastatic reactivation in the lung, bone, and brain. Bioinformatic analyses and pathological studies corroborate the clinical relevance of these findings. We conclude that non-canonical DDR1 signaling enables breast cancer cells to exploit the ubiquitous interstitial matrix component collagen I to undergo metastatic reactivation in multiple target organs.