Jian Zhang, PhD
Assistant Professor
Biomedical Engineering
College of Engineering
University of Arkansas
Thematic Area: Using engineering, biology, and computation approaches to understand the mechanobiology of cancer, with a specific focus on cancer mechano-metabolism
Clustering and inter-cellular interactions often make tumor cell clusters and micrometastases more invasive, and proliferative, and survive better than individual tumor cells. While it is known that micrometastases exhibit distinct metabolic programs compared to primary tumor cells in breast cancer and that cancer cells can adapt their metabolism to the local tumor microenvironment, it is not clear whether this metabolic adaptation is related to cell clustering. To answer this question, this project proposes to engineer the size, shape, composition, and cell-cell interaction of cell clusters using micropatterning, microfabrication, and biological interventions, and use these engineered clusters to systematically assess the regulation of tumor bioenergetics by cell clustering.
Given the recent work showing that cadherin-mediated forces can activate intracellular metabolic flux and increase ATP production and that dysregulated bioenergetics is a hallmark of cancer, we hypothesize that clustering gives a metabolic advantage to cell groups via cell-cell interactions, which may then lead to a metastatic advantage of tumor clusters over individual tumor cells. We will investigate:
- Global Effect: the effect of cell clustering on the bioenergetics of the cluster as a whole
- Local Effect: the effect of cell clustering on the bioenergetics of individual cells within the cluster
- The role of intercellular heterogeneity on the bioenergetics of cell clusters
We will control cell clustering using a combination of engineering and biological approaches and measure the bioenergetic output of the cell clusters with Seahorse extracellular flux assay, label-free multiphoton microscopy of NADH/FAD autofluorescence, and confocal microscopy in combination with genetically encoded metabolic sensors. The proposed study will establish engineered cell culture platforms that systematically control cluster size and shape that will overcome the current limitations and provide great insights into how cluster size, shape, and cell-cell interactions regulate the bioenergetic output. As therapeutics that are effective for single cells may not work for tumor cell clusters, the successful completion of this project and future work related to this project will allow the development of efficient cancer therapies to counter cancers as it relates to tumor cell clustering, micrometastasis, metabolic adaptation, and therapeutic resistance.