Jagged1 regulates extracellular matrix deposition and remodeling in triple-negative breast cancer

Abstract

The extracellular matrix (ECM) in the tumor microenvironment plays an essential role in cancer progression. High expression of Jagged1 correlates with poor patient survival and promotes in vivo tumor growth and invasion in triple-negative breast cancer (TNBC). Using transcriptomics, proteomics, and imaging of cancer cell/fibroblast co-cultures, both in vitro and in vivo, we demonstrate that Jagged1-mediated crosstalk between TNBC cells and fibroblasts enhances myofibroblast activation, collagen deposition, and alignment of ECM fibers. Jagged1 increases transforming growth factor beta (TGF{beta}) activity in fibroblast co-cultures and the Jagged1-induced ECM alignment can be prevented by a TGF{beta} inhibitor. Thus, Jagged1 regulates ECM remodeling upstream of TGF{beta}. Furthermore, higher substrate stiffness increases Jagged1 expression, pointing towards a feed-forward loop between Jagged1, ECM stiffness, and TGF{beta}. With the emergence of safe therapeutics targeting specific Notch ligands and receptors, Jagged1 modulation may offer a path to therapeutically target invasive breast cancer.