Tissues are collections of cells that operate together to accomplish a common biological task. The structure of a tissue is known to have an important impact on cancer progression, and it is known that neighboring healthy cells within a tissue can "peer pressure" cells that would otherwise divide and become tumors into behaving normally. Mutations in a gene known as Ras are associated with many different types of cancer, but, for some reason, they are not often observed in breast cancer. We hypothesize that one reason for this observation may be that breast tissues "peer pressure" cells with Ras mutations into behaving. We propose to study whether this is the case by using techniques developed in the Gartner Lab to assemble cells into model microtissues like ducts. We can then test the effect of the shape and size of these microtissues on how cells with Ras mutations are tolerated within those structures. By understanding the reasons that Ras mutations do not often lead to breast cancer, we may find out how other cancer-causing mutations avoid suppression by their neighbors. This, in turn, may uncover new avenues to suppress tumor growth in other clinically relevant. In order to study the effects of cell shapes on tissue response to a Ras-mutated cell, I propose to develop a new technique for preparing of well defined, biologically relevant, shaped tissues. To do this, I will prepare degradable scaffolds onto which relevant breast tissue cells can be assembled. After the scaffold is degraded, a hollow structure of cells with the desired shape will remain. This technique will allow me to control the size and shape of the tissues being studied in a way that has not previously been achieved. My personal research experience is in the area of materials chemistry and its use in drug deliver and cancer immunotherapy. My future research goals are to combine my knowledge of materials science with the molecular biology, chemical biology, and tissue engineering experience I will acquire over the course of this fellowship. I will then be able to lead my own interdisciplinary research projects that will hlp to unlock the remaining mysteries in cancer biology and develop new areas for the prevention and treatment of all forms of cancer.
Learning what effects structure and shape have on tissue response to tumorigenic mutations will advance our understanding of how tissues regulate the behaviors of their cellular constituents in the context of cancer. It may also provide insight into why certain genetic abnormalities seem to be associated with particular tissue- specific cancer types. Together, this knowledge may provide new targets in the microenvironment for preventing certain malignant behaviors, and may advance our ability to diagnose and stage the most dangerous cancers.
|Broaders, Kyle E; Cerchiari, Alec E; Gartner, Zev J (2015) Coupling between apical tension and basal adhesion allow epithelia to collectively sense and respond to substrate topography over long distances. Integr Biol (Camb) 7:1611-21|