Despite the widespread acceptance that cell-to-cell variability is a defining feature of cancer, much remains unknown about stem cell-like cancer cells hypothesized to be responsible for both metastasis and drug resistance (Marusyk, Almendro, and Polyak 2012). Few analytical techniques exist that can quantify single cell drug uptake, hindering progress towards decoding how cancer cells evade therapeutics.
Our project sought to address the dearth of analytical chemical methods available for single cell analysis by employing accelerator mass spectrometry (AMS) to directly quantify chemotherapeutic uptake in single cells. We have successfully built a platform to measure single cells with Lawrence Livermore National Laboratory's biological AMS instrument, and we have developed new methods to further fractionate cell contents that could be used in conjunction with AMS to quantify drug action. Using our platform, we demonstrated correlation between single cell measurements and population-averaged means. Next, we measured single breast cancer cells treated with carboplatin, a first line chemotherapeutic, after four, twelve, and twenty-four hours of exposure. We found some evidence of a small population of cells present at twelve hours that had a higher amount of the drug, suggesting that bulk averages may not accurately describe the drug uptake in this system.
Our research advances Livermore's core capabilities in biosciences and bioengineering and advances the Department of Energy goal to build a bridge between fundamental science research and beneficial technology innovations. Our project leveraged the Laboratory's unique Bio-AMS at the Center for Accelerator Mass Spectroscopy (CAMS). Our results further elevate Livermore as an authority in Biological AMS. Interest in this project expressed by collaborators in the UC Davis Comprehensive Center Consortium (UCDCCC) resulted in the award of a joint pilot grant from UCD to a Livermore team, including the project PI, augmenting Livermore's expertise and access to clinical samples.
Marusyk, Andriy, Vanessa Almendro, and Kornelia Polyak. 2012. "Intra-Tumour Heterogeneity: A Looking Glass for Cancer?" Nature Reviews Cancer 12 (5): 323. https://doi.org/10.1038/nrc3261.
Fong., E., et al. 2018. "Empowering Accelerator Mass Spectrometry to Find Single Cells Responsible for Cancer Drug Resistance." 5th Annual Southern California Micro and Nanofluidics Symposium, Arcadia CA, August 2018. LLNL-ABS-756245.
——— . 2018. "Empowering Accelerator Mass Spectrometry to Quantify Single Cell Chemotherapeutic Uptake." SelectBIO World Congress: Single Cell Analysis Summit 2018, Coronado CA, October 2018. LLNL-POST-752500.
——— . 2019. "Quantifying Drug Delivery to Single Tumor Cells in a 3D in Vitro Model of the Tumor Microenvironment." 25th Annual Cancer Research Symposium, Sacramento, CA, September 2019. LLNL-POST-789237.
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