Abstract
Coherence-gated dynamic light scattering captures cellular dynamics through ultra-low-frequency (0.005–5 Hz) speckle fluctuations and Doppler shifts that encode a broad range of cellular and subcellular motions. The dynamic physiological response of tissues to applied drugs is the basis for a new type of phenotypic profiling for drug screening on multicellular tumor spheroids. Volumetrically resolved tissue-response fluctuation spectrograms act as fingerprints that are segmented through feature masks into high-dimensional feature vectors. Drug-response clustering is achieved through multidimensional scaling with simulated annealing to construct phenotypic drug profiles that cluster drugs with similar responses. Hypoxic vs. normoxic tissue responses present two distinct phenotypes with differentiated responses to environmental perturbations and to pharmacological doses.
Highlights
We demonstrate the use of tissue dynamics spectroscopy as a new phenotypic screening
Received 24 Jul 2012; revised 3 Oct 2012; accepted 3 Oct 2012; published 15 Oct 2012 1 November 2012 / Vol 3, No 12 / BIOMEDICAL OPTICS EXPRESS 2828 technology, based on spectrogram feature extraction and dimensionality reduction, and we study the phenotypic drug response of normoxic tissue relative to hypoxic tissue inside multicellular tumor spheroids
Because of our knowledge of the physiological processes of apoptosis relative to necrosis, we tentatively assign this phenotypic difference to apoptosis in the shell vs. necrosis in the core
Summary
Drug discovery has placed less emphasis on biochemical target-based assays and relied more on live cell-based assays because they more accurately measure how signaling pathways respond to drugs at a systems-biology level [1]. Altered physiological behavior is the result of drug-altered signaling pathways, affecting organelle and vesicle activity, intracellular organization and cytoplasmic streaming, cell division, membrane undulations, cell contacts and cell shape changes While these dynamic processes can be viewed in two-dimensional monolayer using conventional microscopies, it is more biologically relevant but challenging to extract subcellular motion up to a millimeter deep inside three-dimensional tissue culture. Received 24 Jul 2012; revised 3 Oct 2012; accepted 3 Oct 2012; published 15 Oct 2012 1 November 2012 / Vol 3, No 12 / BIOMEDICAL OPTICS EXPRESS 2828 technology, based on spectrogram feature extraction and dimensionality reduction, and we study the phenotypic drug response of normoxic tissue relative to hypoxic tissue inside multicellular tumor spheroids
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