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Defining the mechanism of dynamic matrix stiffening-driven lung cancer metastasis

Institution: University of California, San Diego
Investigator(s): Daehwan Kim,
Award Cycle: 2019 (Cycle 30) Grant #: T30FT0896 Award: $193,320
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
Lung cancer is the leading cause of cancer deaths in the United States and worldwide, and the overall 5-year survival rate is approximately 15%. The most common form of lung cancer is non-small cell lung cancer, which accounts for 85-90% of lung cancer cases. Among the various factors related to the lung cancer progression, smoking is a major cause of lung cancer initiation. In particular, smoking-induced pulmonary fibrosis is tightly associated with lung cancer development. Compared with normal tissue, cancerous lung tissues present a 10-50 fold increase in tissue rigidity, and this increasing matrix stiffness could epithelial-mesenchymal transition (EMT). EMT is a complex coordination of a network of transcription factors and signal transduction pathways leading to altered expression of genes in cell adhesion, differentiation, and motility with an important implication for driving tumor progression. Prior models for EMT and matrix stiffness studies rely on static hydrogel in which cells experience defined matrix rigidities. These materials lack dynamic physical properties to mimic in vivo development from soft normal lung tissues to rigid lung tumors over time. Despite the critical functions of mechanical force in regulating cancer invasion and metastasis, how tissue rigidity or stiffness regulates lung cancer metastasis at the molecular level remains largely unknown. The main purpose of this proposal is to understand how increasing matrix stiffness promotes lung cancer metastasis through EMT. Recently, we developed a new hydrogel that can be stiffened “on demand” overtime. Since lung tissue is soft for decades prior to stiffening, this material directly mimics such physical change during tumor progression. Using this novel system, I plan to identify novel rigidity-regulated mechanotransduction pathways controlling lung cancer metastasis compared with normal lung epithelial cells. In addition, I will characterize the molecular functions of these proteins. Finally, I will test whether inhibiting the functions of these proteins could block EMT and metastasis of lung cancer in 3D condition and mice model. I hope that my research will provide a better understanding of EMT signaling in lung cancer upon matrix stiffening, and it will be key to the development of new therapeutic strategies to improve the prognosis of patients with this condition.