DCAF8L1 induces branching morphogenesis and hollow acinar structures remodeling of MCF10A cells in 3D culture by upregulating DDR1.

Mammary morphogenesis is a highly coordinated process involving cellular differentiation, proliferation, and organization to form a bilayered epithelial network of ducts and lobules within the stromal matrix. Here, we identified the DDB1 and CUL4 associated factor 8-like 1(DCAF8L1) as a novel regulator of mammary morphogenesis. To investigate its role, we established stable DCAF8L1-expressing MCF10A cell lines, which normally lack DCAF8L1 expression. Overexpression of DCAF8L1 enhanced cell proliferation, migration, and induced branching morphogenesis and vacuolar structure assembly in three-dimensional (3D) culture. Subsequently, transcriptomic and proteomic analyses identified the discoidin domain receptor tyrosine kinase 1 (DDR1) as a key downstream effector of DCAF8L1. Further investigation revealed that DCAF8L1 upregulates DDR1, leading to activation of the Notch signaling pathway. These findings suggest that DCAF8L1 drives mammary branching morphogenesis and vacuolar structure assembly via DDR1-mediated Notch activation in 3D-cultured MCF10A cells.