Regulation of Breast Cancer Stem Cell by Tissue Rigidity
Annual rept. 1 Jun 2014-31 May 2015
CALIFORNIA UNIV SAN DIEGO LA JOLLA
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The presence of a fibrotic focus in breast tumors is associated with a 10-50-fold increase in tissue stiffness and correlates with distant metastasis and poor outcome. Recent studies indicate that increasing tissue rigidity promotes breast cancer progression, however the underlying molecular mechanism is largely unknown. Breast cancer stem cells have both long-term self-renewal capacity and the ability to initiate tumors. In this proposal, we hypothesize that tissue rigidity regulates breast cancer stem cell properties and function, therefore assisting breast tumor development and promoting chemoresistance. Our major findings are the following. 1. We developed two hydrogel systems and determined their mechanic properties. 2. We found that increasing tissue rigidities promoted breast cancer stem cell properties. 3. We uncovered that a mechanistic link between tissue rigidity and breast cancer stem cells was via the activation of the EMT program. 4. We found that the EMT-inducing transcription factor Twist1 was essential for high tissue-rigidity-induced EMT. 5. We identified a novel Twist1G3BP2 mechanotransduction pathway that responds to increasing matrix stiffness in the tumor microenvironment to drive EMT, cancer stem cell properties, invasion, and metastasis. Together, these results indicate that increasing matrix stiffness promotes EMT via an integrin and Twist1-dependent pathway to regulate breast cancer stem cell function, thus impacting breast cancer progression.
- Anatomy and Physiology
- Medicine and Medical Research