Engineering the Cancer Microenvironment

项目总结/文摘

PROJECT SUMMARY/ABSTRACT 90% of cancer related deaths occur as a result of metastasis12,17. The metastatic cascade is a complex series of events initiated by changes of the cancer cell phenotype, giving rise to invasive properties through a process known as the epithelial-to-mesenchymal transition (MET)7, 14, 15. Once metastatic cells are in the circulatory system, the cells must extavasate into distant tissues, resulting in the formation of secondary tumors. When cancer cells arrive in the new tissues, their behavior is driven in part by the non-soluble signaling of extracellular matrix (ECM) proteins within the microenvironment10. Currently, no system exists that can recreate this sequence of soluble and non-soluble signaling events, slowing the development of effective therapies. Therefore, in collaboration with Dr. Joerg Lahann, I propose to develop an engineered cancer microenvironment that can be used to evaluate the effects of specific microenvironmental cues on cancer cell behavior. A 3D polymer fiber writing system has recently been developed within the Lahann lab that allows fabrication of hyper-porous polymer scaffolds with patterned fiber architectures. This system enables precise control over a range of characteristics including the scaffold physical/mechanical properties, and facilitates coating with networks of various ECM proteins (in their 3D biologically active conformations). These modular scaffolds can be seeded with a variety of cell types, enabling investigation of cell-cell or cell-matrix interactions. As such, this tailorable platform technology could be designed to mimic key elements of the native cancer microenvironment. During the mentored K99 phase of this proposal, the mechanical properties and ECM composition will be tuned to mimic elements of primary and metastatic tumors. The effect that changes in the cancer microenvironment has on cancer cell proliferation, cancer stem cell distribution, and phenotype will be evaluated. Furthermore, these environments will also be used to culture primary cancer cells obtained from pleural effusions. The effect of the ECM composition on cancer stem cell distribution and senescence of primary patient samples will be evaluated. The cellular components of the cancer microenvironment and the pre-metastatic niche will also be investigated. Transitioning into independence in the R00 phase, I will evaluate the in vivo efficacy of the engineered cancer microenvironments to promote secondary tumor formation. This K99/R00 award would enable the creation of a system that could recapitulate metastatic cancer cell invasion in vivo, providing a means by which the molecular and cellular basis of cancer can be better understood. If successful, this system will provide a platform technology for combinatorial drug screening and may lead to the development of personalized cancer therapies. At the University of Michigan, I have access to world-class facilities as well as an unparalleled collection of leaders in the field of cancer research. I have assembled an distinguished advisory committee to guide my research and facilitate my transition to independence. Dr. Joerg Lahann, Director of the Biointerfaces Institute and expert in fluid-based processes for polymer fiber and particle fabrication, will serve as my primary mentor. Dr. Max Wicha, Director of the University of Michigan Comprehensive Cancer Center and leader in the field of tumorigenesis, will serve as my co-mentor. Other distinguished members of my mentoring team include Dr. Diane Simeone, Director of the Translational Oncology Program and expert in pancreatic cancer tumorigenesis, Dr. Gary Luker, is an expert in molecular imaging systems and mouse models of breast cancer, and Dr. Jan Stegemann, expert in the development of 3D tissue engineered environments and ECM signaling. Opportunities provided by this award, in combination with the world-class facilities and mentoring team at the University of Michigan, would enable me to achieve both my short-term goal of becoming a tenure-track assistant professor, as well as my long-term goal of developing technologies that will help patients suffering from aggressive forms of cancer improve their therapeutic outcomes and overall quality of life.