Regulation of Mammary Epithelial Signaling by Local Matrix Stiffness

Investigator: Thea D. Tlsty, PhD
Sponsor: University of California Irvine (UCI)

Location(s): United States


The primary research objective of this NSF-NCI Physical and Engineering Sciences in Oncology (PESO) joint research grant is to test the hypothesis that stiff stoma sensitizes mammary epithelial cells (MECs) to tensile forces, where tensile forces lead to integrin oligomerization and activation of downstream signaling pathways known to promote invasive cancer. The hypothesis will be tested on both isolated MECs and acini formed within a 3-D extracellular matrix (ECM). This research combines a powerful set of methods to investigate this hypothesis including: 3-D traction force microscopy for the estimation of adhesion forces, optical tweezers active microrheology for the in situ measurement of stiffness, a shear gradient device for establishing gradients of stretch and stiffness within naturally derived ECMs, and real-time imaging of cellular signals to determine how mammary acini respond to instantaneous changes in ECM-coupled tension. Correlations will be sought between ECM stiffness and the degree of signaling in response to tensile forces.

Successful completion of the research activities will have a far-reaching impact on cancer research. A better understanding of MECs' response to stretch in both a 2-D and 3-D context will help us understand how they may respond to forces while confined to an acinus, persisting in a hyperplastic mass or invading the stroma. Importantly, findings will provide a critical puzzle piece linking mammographic density, stromal stiffness, forces, integrin-mediated signaling, and the progression of metastatic breast cancer. The methodologies to be developed will be useful in the study of other forms of cancer and in many other areas of research in need of a mechanical perspective including regenerative medicine, stem cell biology, developmental biology, cardiovascular biology and tissue engineering. The educational components of this proposal include the integration of research into a multidisciplinary course, the involvement of undergraduate students through short-term summer projects, and the participation of underrepresented engineering students with the support of the NSF funded California Alliance for Minority Participation in Science, Technology, Engineering and Math (CAMP). Findings will be broadly disseminated to the public through outreach programs, lectures and a museum exhibit.