Jagged1 regulates extracellular matrix deposition and remodeling in triple-negative breast cancer
Marjaana Parikainen, Ujjwal Suwal, Pekka Rappu, Jyrki Heino, Cecilia M. Sahlgren
TL;DR
This study shows that Jagged1 promotes aggressive breast cancer by altering the tumor environment and increasing ECM stiffness through TGFβ activity.
Contribution
The paper reveals a novel mechanism where Jagged1 regulates ECM remodeling via TGFβ in triple-negative breast cancer.
Findings
Jagged1 enhances myofibroblast activation and ECM alignment in fibroblast-cancer cell interactions.
Jagged1 increases TGFβ activity, and TGFβ inhibition blocks Jagged1-induced ECM changes.
Higher substrate stiffness up-regulates Jagged1, creating a feed-forward loop with TGFβ.
Abstract
The extracellular matrix (ECM) and tumor microenvironment heterogeneity drive cancer progression and treatment resistance. High Jagged1 expression correlates with poor patient survival and promotes tumor growth and invasion in triple-negative breast cancer (TNBC). Using transcriptomics, proteomics, and imaging of cancer cell/fibroblast cocultures in vitro and in vivo, we demonstrate that Jagged1-mediated cross-talk between TNBC cells and fibroblasts enhances myofibroblast activation, collagen accumulation, and alignment of ECM fibers. In single-cell RNA sequencing data of TNBC tumors, high Jagged1 expression gives rise to a myofibroblast subpopulation previously associated with enhanced invasion. Jagged1 increases transforming growth factor–β (TGFβ) activity in fibroblast cocultures, and TGFβ inhibition prevents the Jagged1-induced ECM alignment. Thus, Jagged1 regulates ECM remodeling…
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Taxonomy
TopicsCellular Mechanics and Interactions · Cancer Cells and Metastasis · Cell Adhesion Molecules Research