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Title: Integrin-Linked Kinase Regulates TGFβ-Induced Phenotypes on Stiff Extracellular Matrix
Authors: Li, Shiyi
Advisors: Nelson, Celeste M.
Department: Chemical and Biological Engineering
Certificate Program: Global Health and Health Policy Program
Class Year: 2017
Abstract: Among the many microenvironmental factors known to regulate cancer progression, mechanical properties of the extracellular matrix (ECM) have been shown to play a prominent role in promoting tumor malignancy. Enhanced stromal tissue stiffness has not only been observed around most tumors, but is also causally linked to enhanced invasive potential. Uncontrolled cellular proliferation and epithelial-mesenchymal transition (EMT), a process by which epithelial cells acquire motile mesenchymal characteristics, are two key examples of malignancy-enhancing events. Among the many signaling pathways that could regulate EMT or proliferation, the transforming growth factor-β (TGFβ) pathway - which is not only one of EMT’s most important biological inducers but also a potent growth inhibitor - provides key insights into how these processes are regulated by ECM stiffness. This study revealed that TGFβ-induced EMT and growth inhibition are enhanced by ECM stiffness and that the integrin-linked kinase (ILK) – a protein closely implicated in cellular mechanotransduction – plays a causal role in this relationship. Here, I found that inhibiting ILK blocked the enhancement of TGFβ-induced EMT on stiff ECM via Smad and Snail signaling. Moreover, while the expression of E-cadherin – an intercellular junctional protein – is downregulated by TGFβ, ILK knockdown abrogated this relationship on stiff ECM. Finally, inhibiting ILK impaired TGFβ-induced growth inhibition on stiff ECM. Collectively, these observations demonstrated that ILK plays a causal role in the enhancement of TGFβ-induced EMT and growth inhibition by ECM stiffness. Clinically, the targeting of ILK thus becomes a promising therapeutic approach to reverse the upregulation of malignant cancer characteristics by ECM stiffness.
Type of Material: Princeton University Senior Theses
Language: en_US
Appears in Collections:Chemical and Biological Engineering, 1931-2022
Global Health and Health Policy Program, 2017-2022

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