CAREER: Force-Generating Mechanisms Responsible for Matrix-Dependent Compressive Mechanical Feedback During Tumor Growth

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Growth is a necessary process to develop the organs and structures of the body. It is a complex process involving signals inside cells, between cells, and between cells and their surrounding matrix. During growth, cells divide -- leading to expansion of the organ or structure that pushes against the matrix that surrounds it. The matrix acts to constrain the dividing cells. This expansion against the matrix results in a compressive force being generated on the cells. It is not currently understood how this constraint-induced compression affects future cell division and growth. However, it is known that diseases like cancer, which lead to the seemingly chaotic growth of tumors, often initiate and flourish in matrices that are significantly stiffer than healthy matrices. This Faculty Early Career Development Program (CAREER) award project will seek to determine how cells decide how much constraint-induced compression is healthy for them to grow against and how tumor cells evade such signals. The advancement in knowledge expected from this award can then be applied to support development of new treatment and characterization systems for cancer. The project will also engage, motivate, and educate future scientists and the community on the importance of mechanics in health and disease. These educational and outreach activities include three interactive modules for young high school students, participating in residential research summer programs for high school students, mentoring undergraduate student researchers, developing a graduate-level curriculum, and even collaborating with dancers to develop performances that communicate concepts of biomechanics to a broad audience.The overall research goal of this project is to study tissue growth in malignant tissue as a function of the mechanical properties of the extracellular matrix, focusing on understanding the signaling pathways and cytoskeletal network mechanics through which cells transduce mechanical constraint during tissue growth. This is supported through three research objectives. The first objective will determine the proliferative potential and cell- and tissue-scale morphological development of breast cancer cells of increasing aggressiveness during mechanically constrained growth using well-defined hydrogel matrices. Measurements related to cellular and tissue morphology, as well as cellular division, will be quantified using time-lapse confocal microscopy as a function of the number of cells present and the matrix mechanical properties. The second objective will compare tissue- and cell-scale stress fields in the matrix and tissue for the panel of breast cancer cells of increasing aggressiveness. This will be done through imaging of tissue deformation caused during growth using fluorescent microbeads co-embedded in the matrix with the cells. The final objective seeks to determine the mechanism by which cells transduce mechanical constraint during division in tissue growth by examining the expression of proteins that are involved with force generation and sensing during cellular division and partially inhibiting those proteins to discern their individual roles. The scientific impact of this work will be significant, as it will significantly contribute to the fundamental understanding of tumor growth and development -- key questions that must be answered to allow future developments in cancer treatment.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.