Date of Award

Spring 5-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Characteristics of breast tumor stroma, including altered collagen architecture and increased stiffness, are known to contribute to tumor invasion and metastasis. However, the cellular and molecular mechanisms by which these changes occur are not fully understood. To address this question, we used a mouse genetic model to delete Discoidin Domain Receptor 2 (DDR2) from mouse tumor stromal cells and interrogated breast cancer associated fibroblasts (CAFs) to determine the molecular events downstream of DDR2 action that may lead to changes in the tumor extracellular matrix (ECM). Our work revealed that the action of DDR2 in breast stromal cells is required for tumor lung metastasis but does not affect tumor growth or latency. Interestingly, stromal DDR2 action led to lengthened, thickened, and straightened collagen fibers while also stiffening the tumor. Tumor stiffness was found to be greatest at the invasive front of the tumor, closest to the tumor/stromal boundary; this finding was obliterated in tumor stromas without DDR2. Selectively studying CAFs ex vivo, we found that DDR2 promotes increased cellular contraction and traction force. Super-resolution microscopy analysis of focal adhesion complexes in CAFs revealed that DDR2 collagen binding facilitates focal adhesion maturation and enhances integrin ß1 activation through recruitment of Talin11. We also find that DDR2 regulates Rap1 activation, suggesting a mechanism by which Talin11 is activated downstream of DDR2 collagen binding. Taken together, these results identify DDR2 as a novel mechanosensing/mechanotransducing cell surface receptor that promotes tumor invasion and metastasis by acting in tumor stromal CAFs to control ECM remodeling, in part through regulation of integrin ß1 activity via inside-out signaling.

Language

English (en)

Chair and Committee

Gregory D. Longmore

Committee Members

Robert Mecham, Sheila Stewart, David DeNardo, Jeffrey Miner,

Comments

Permanent URL: https://doi.org/10.7936/47gw-h415

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