The Notch ligand Jagged1 regulates extracellular matrix production and organization in triple-negative breast cancer

The extracellular matrix (ECM) in the tumor microenvironment plays an essential role in the progression of cancer. Here, we show that expression of the Notch ligand Jagged1 correlates with poor patient survival in aggressive breast cancer and that Jagged1 promotes in vivo tumor growth and invasion of triple-negative breast cancer cells. Using transcriptomics, proteomics, and imaging approaches of cancer cell/fibroblast co-cultures, both in vitro and in vivo, we demonstrate that Jagged1 drives fibroblast activation, increased collagen deposition, and aligned organization of ECM fibers. Jagged1 increases transforming growth factor beta (TGFß) related signaling in fibroblast co-cultures and the Jagged1-induced ECM alignment can be prevented by a TGFß inhibitor. Thus, Jagged1 regulates ECM remodeling upstream of TGFß. With the emergence of safe therapeutics targeting specific Notch ligands and receptors, Jagged1 modulation may offer a path to therapeutically target invasive breast cancer. Overall design: RNA-seq profiling of wildtype MDA-MB-231 breast cancer cells and their derivative cell lines (Jag1KO, Jag1KO+rescue, Jag1KO+ctrl, siCtrl, and siJag1) with altered expression of JAG1, grown for 7 days as 3D Matrigel cultures. 3 biological replicates of each sample.