Understanding the role of Notch receptors in mechanotransduction

Project Leaders: Dr. Wen Yih Aw, HIRING GRADUATE STUDENTS

Authored by: Dr. Wen Yih Aw

Our group seeks to understand how cells integrate chemical and mechanical signals to adopt specifics cell fates and tissue patterns during tissue development, homeostasis, and diseases. In particular, we are interested in understanding the role of Notch receptor signaling in mechanotransduction and transcriptional regulation of vascular function. We have uncovered a role of Notch transmembrane domain (cortical signaling) in driving flow mediated adherens junction assembly, and we are currently exploring the crosstalk and synergy between Notch cortical and transcriptional signaling in regulating endothelial cell phenotype and function: i) maintenance of barrier function in response to flow and wound, ii) tip and stalk cells selection during angiogenesis, and iii) collective cellular migration during angiogenesis.

Key collaborators:

Matthew Kutys, PhD - Asst. Prof. of Cell and Tissue Biology, UCSF

Victoria Bautch, PhD - Professor of Biology, UNC

Key resources:

UNC Zebrafish Core

Funding:

AHA Career Development Grant CDA857738 (PI: Polacheck)

DAPT_DAPI-VE-Composite_RGB.jpg

3D engineered blood vessels serve as a model system for investigating the effects of Notch activity on the establishment and maintenance of endothelial cell-cell junctions.

Integrin signaling in response to interstitial flow

Project Leaders: HIRING GRADUATE STUDENTS AND POSTDOCS

During solid tumor growth, tumor-induced angiogenesis, desmoplasia, and the collapse of draining lymphatics cause increased interstitial fluid pressure (IFP) in the tumor microenvironment. This elevated pressure causes large pressure gradients and elevated interstitial fluid flow at the tumor margin. This interstitial fluid flow is different than the flow of blood in the vasculature. The fluid originates within the tumor and creeps through the tissue, between cells and proteins in the tumor to drain in normal tissue surrounding the tumor. Clinically, elevated IFP correlates with increased metastasis and poor prognosis. Metastasis is the leading cause of cancer-related death, so IFP is a potential tool for clinicians to judge severity of cancer, but the mechanisms by which these pressures and flows contribute to the molecular and cellular events of the metastasis remain unknown. 

To investigate the role of IFP and interstitial flow in cancer progression and metastasis, we are developing human vascularized tumor models and leveraging these models to study how flow alters cell-cell and cell-matrix adhesion signaling in tumor cells and stroll cells, including fibroblasts. We are also interested in understanding the effects of interstitial flow on immune cell trafficking and surveillance in the tumor microenvironment. The long-term goals of this work are to understand the molecular basis for the connection between IFP and patient prognosis and to inform interventional strategies for preventing metastatic disease. 

Key resources:

Chapel Hill Analytical and Nanofabrication Laboratory

Lineberger Cancer Center

Funding:

NIH MIRA 1R35 GM142944-01 (PI: Polacheck)

Composite_MatrixGap.jpg

We use live cell confocal microscopy with 3D microfluidics to image the response of tissue-resident cells to gradients in interstitial pressure and to interstitial flow. These data then inform computational models to understand how determine how these effects might regulate cellular responses in the complex native microenvironment.