Role of Aging and Diabetes Related Changes to the Extracellular Matrix on Cancer Invasion

Cancer becomes life-threatening when tumor cells spread from the original tumor to other parts of the body. This spreading process depends not only on the cancer cells themselves, but also on the surrounding tissue called the extracellular matrix (ECM). The ECM provides physical support to cells. The structure and mechanical properties of ECM change with age and with diseases such as diabetes. These changes in ECM may make it easier for tumor cells to spread into healthy tissue, but the underlying mechanisms are not well understood. This project will study how aging- and diabetes-related changes in the ECM affect cancer cell invasion in breast cancer. The research will combine laboratory experiments with mathematical modeling to predict condition under which cancer cells are most likely to spread and metastasize. The project will also include education and outreach activities that will have broad societal impact. The project will train K-12 to graduate students in interdisciplinary research at the intersection of engineering and cancer biology. This project will establish a quantitative, energy-based framework for predicting tumor invasion as a function of ECM physical properties, with a particular emphasis on changes associated with aging and diabetes. Aging and diabetes alter key features of the ECM, including collagen concentration, crosslinking, stiffness, pore size, and structural anisotropy, creating complex mechanical environments that regulate cell behavior. However, existing studies report conflicting conclusions regarding how ECM mechanics influence cancer invasion, underscoring the need for a unifying physical framework. The project will integrate controlled experiments, thermodynamic modeling, and computational analysis to quantify the energetic barriers that govern whether cancer cells invade the surrounding matrix. By measuring how ECM physical properties regulate cellular forces, shape changes, and cell-matrix interactions, the research will compute the total free energy of the tumor-ECM system and use it to predict invasion likelihood. These predictions will be tested using 3D bioprinted tumor spheroid platforms that allow independent control of ECM stiffness, pore size, composition, alignment, degradability, and the ability of cells to mechanically remodel their surroundings. The expected outcomes include a predictive framework linking ECM physical state to cancer invasion, mechanistic insight into how aging and diabetes alter tumor progression, and experimentally validated models of pathological tissue environments. Together, these results will advance fundamental understanding of cancer mechanobiology while laying a quantitative foundation for future strategies that target the tumor microenvironment. 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. NSF Award ID: 2529738 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Farid Alisafaei | Institution: New Jersey Institute of Technology, NEWARK, NJ | Award Amount: $529,945 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2529738 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2529738.html