Biology subjects

Sahlgren, C. M.

Publications and source records attributed to Sahlgren, C. M..

3 recordsLinked to original sources

bioRxiv2025

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

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.

cancer biology↗

bioRxiv2025

Mechanosensitive interactions between Jag1 and Myo1c control Jag1 trafficking in endothelial cells

Morphogenesis of the cardiovascular system is responsive to hemodynamic cues. In endothelial cells the organization of morphogenic signaling proteins can be regulated by membrane presentation and internalization of proteins. How these signaling proteins are regulated by hemodynamics is unclear. One of the signaling proteins that is regulated by hemodynamics is Jagged1, a ligand in the Notch pathway. Here we set out to identify factors that differentially interact with Jagged1 in response to shear stress exposure, by combining an orbital shaker as a shear stress platform with endothelial cells expressing Jagged1 coupled to an APEX2-tag for proximity labeling. Myo1c was identified and confirmed through coimmunoprecipitation as a Jag1 interacting factor under static conditions, with reduced interaction after exposure to shear in endothelial cells. We showed that Jagged1 polarized downstream of shear followed by nucleograde transport of Jagged1. Myo1c knockout inhibited shear-induced Jagged1 polarization and consequent nucleograde transport. Further, Myo1c knockdown reduced membrane levels of Jagged1 under static conditions, but not under shear conditions. Together, our data reveal a role for Myo1c in the hemodynamic control of Jagged1 localization in endothelial cells.

cell biology↗

bioRxiv2024

Jagged1 is a Notch-independent mechanotransducer in endothelial cells

The Notch signaling pathway plays a crucial role in regulating endothelial biology. Notch signaling is sensitive to hemodynamic forces and governs mechanically-driven cardiovascular development, physiology, and remodeling. However, the mechanisms by which mechanical forces integrate with the Notch pathway remain largely unknown. Here, we uncover a non-canonical role for the Notch ligand Jagged1 in regulating the activity of mechanosensitive kinases in endothelial cells. We show that stress induces expression and relocalization of Jagged1 to cell junctions downstream of flow. Jagged1 expression under stress demonstrates magnitude dependence and peaks at 0.8-1Pa without impacting Jagged1s Notch-activation potential. On the contrary Jagged1 regulates the activity of mechanosensitive kinases. Deletion of Jagged1 reduces the activity of VEGFR2 and ERK in vitro and diminished ERK activity in zebrafish embryos without affecting canonical Notch signaling. Furthermore, the direct physical stimulation of Jagged1 using antibody-conjugated beads triggers the activation of VEGFR2 and ERK, mediated by Jagged1-induces Src activation. Taken together, we demonstrate a novel non-canonical role for Jagged1 as a regulator of the activity of pathways involved in endothelial mechanotransduction.

cell biology↗