(387a) Award Submission: Overcome Drug Resistance of Cancer Cells By Confining, Perturbing and Analyzing Them in Nano-Liter Chambers One Cell at a Time

Tumor cells develop resistance to many therapies. And it is a major problem across many non-surgical cancers. We find that, multi-functional nanotechnology, when applied onto drug resistance development scenario, could uncover the resistance mechanism and provide rationale for designing effective combination therapy to overcome it.

Although it may take a few months to see the reoccurrence of tumor, yet people recently realize that tumor cells already developed resistance as early as a few days after drug treatment. This is because that tumor cells can easily change its cell state from the original drug sensitive one to a very different one, which allow them to survive under the drug treatment. Therefore, stop the unfavorable cell state transition is required in order to overcome drug resistance. To do that, it is essential to discover the driver regulators that lead the unfavorable cell state changes. Finding the driver regulators are very hard because of 2 major obstacles. Because there are mixtures of different cell states involved in such transition (need to analyze individual cells), and because, within each cell, the regulatory network has many regulators involved (need to characterize many proteins), single-cell proteomic analysis is the best way to study it.

However, single-cell proteomics are extremely hard to implement mainly because the protein amounts in single cells are too little to be detected. Fortunately, this problem could be beautifully addressed by a multi-functional bionanotechnology developed in our lab called single-cell barcode chip (SCBC). This nanotechnology can confine individual cells in nano-liter chamber. Perturbing and lysing single cell within the chamber is also feasible through programming the nano-liter fluid. Consider the nano-liter size of each chamber, small amount of protein from single cell when released within such tiny volume will also have a detectable concentration. Based on such multi-functional, programmable, nano-chamber, many important regulators from each individual cell are quantified simultaneously with the help of arrays of antibodies and nano-probes installed orderly within each chamber.

When applied to tumor cells that are under therapeutic treatment, this powerful nanotechnology enables us to uncover the changes of many important regulators simultaneously across thousands of individual cancer cells. The big data generated from the nanotechnology pinpoint the most important regulators that are driving the initiation of such unfavorable cell state changes, which leads to resistance. Base on the information from the powerful nanotechnology, an effective combination therapy is designed which is experimentally validated to be able to halt the unfavorable cell-state transition and therefore arrested the resistance development.

This powerful nanotechnology could provide deep biological insights that are otherwise impossible to see. The nanotech has the potential to uncover the resistance mechanism across many other cancer types and potentially bring durable therapy response to a broad range of cancer patients. This may usher a new era of nanotech-assisted rational designing of combination therapy.