The impact of non-genetic heterogeneity on cancer cell death

Inde, Zintis; Dixon, Scott J.

doi:10.1080/10409238.2017.1412395

Cited by 42 publications

(38 citation statements)

References 113 publications

(177 reference statements)

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“…Finally, several lines of evidence suggest that drug persistence in cancer cells also relies on a distinct regulatory program [43], and particularly pinpoint two regulatory processes. The first process is epithelial-to-mesenchymal transition (EMT), which causes cells to gradually lose their differentiation status and become more stem-cell like [44].…”

Section: Introductionmentioning

confidence: 99%

Drug persistence – From antibiotics to cancer therapies

Kochanowski

Morinishi

Altschuler

et al. 2018

Current Opinion in Systems Biology

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Drug-insensitive tumor subpopulations remain a significant barrier to effective cancer treatment. Recent works suggest that within isogenic drug-sensitive cancer populations, subsets of cells can enter a ‘persister’ state allowing them to survive prolonged drug treatment. Such persisters are well-described in antibiotic-treated bacterial populations. In this review, we compare mechanisms of drug persistence in bacteria and cancer. Both bacterial and cancer persisters are associated with slow-growing phenotypes, are metabolically distinct from non-persisters, and depend on the activation of specific regulatory programs. Moreover, evidence suggests that bacterial and cancer persisters are an important reservoir for the emergence of drug-resistant mutants. The emerging parallels between persistence in bacteria and cancer can guide efforts to untangle mechanistic links between growth, metabolism, and cellular regulation, and reveal exploitable therapeutic vulnerabilities.

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Section: Introductionmentioning

confidence: 99%

Drug persistence – From antibiotics to cancer therapies

Kochanowski

Morinishi

Altschuler

et al. 2018

Current Opinion in Systems Biology

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“…Heterogeneous cellular phenotypes within one population are common in nature, with drug-induced fractional killing in tumors being one clinically important manifestation (Bigger, 1944;Inde and Dixon, 2018;Niepel et al, 2009;Palmer et al, 2019). Quantifying population-level cell heterogeneity can be laborious, especially when tracking the fate of hundreds of individual cells within a single population.…”

Section: Discussionmentioning

confidence: 99%

“…Rather, we hypothesized that slow FK was due to non-genetic molecular heterogeneity downstream or in parallel to ERK1/2. Several known candidate mechanisms of FK (Inde and Dixon, 2018), including p53 stabilization, cell cycle phase, glycolytic or oxidative metabolism, and reactive oxygen species (ROS) accumulation, did not contribute to MEKi-induced FK ( Figure S3C-J). Thus, the molecular heterogeneity contributing to FK in response to MAPK pathway inhibition appeared to reside elsewhere in the cellular network.…”

Section: Mek1/2 Inhibitors Trigger Slow Fk Not Involving Many Known Mmentioning

confidence: 99%

Large-Scale Analysis of Cell Death Phenotypic Heterogeneity

Inde

Denton

et al. 2020

Preprint

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Individual cancer cells within a population can exhibit substantial phenotypic heterogeneity such that exposure to a lethal agent will kill only a fraction of cells at a given time. Whether common molecular mechanisms govern this fractional killing in response to different lethal stimuli is poorly understood. In part, this is because it is difficult to compare fractional killing between conditions using existing approaches. Here, we show that fractional killing can be quantified and compared for hundreds of populations in parallel using high-throughput time-lapse imaging.We find that fractional killing is highly variable between lethal agents and between cell lines. At the molecular level, we find that the antiapoptotic protein MCL1 is an important determinant of fractional killing in response to mitogen activated protein kinase (MAPK) pathway inhibitors but not other lethal stimuli. These studies lay the foundation for the large-scale, quantitative analysis of cell death phenotypic heterogeneity.3

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“…This is due to the sampling capillary tip's tendency to break if the sample density is high. Therefore, another approach such as the single-probe may be more suitable in such cases 14,15 .…”

Section: Discussionmentioning

confidence: 99%

An Integrated Raman Spectroscopy and Mass Spectrometry Platform to Study Single-Cell Drug Uptake, Metabolism, and Effects

Ali

Abouleila

Germond

2020

JoVE

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Cells are known to be inherently heterogeneous in their responses to drugs. Therefore, it is essential that single-cell heterogeneity is accounted for in drug discovery studies. This can be achieved by accurately measuring the plethora of cellular interactions between a cell and drug at the single-cell level (i.e., drug uptake, metabolism, and effect). This paper describes a single-cell Raman spectroscopy and mass spectrometry (MS) platform to monitor metabolic changes of cells in response to drugs. Using this platform, metabolic changes in response to the drug can be measured by Raman spectroscopy, while the drug and its metabolite can be quantified using mass spectrometry in the same cell. The results suggest that it is possible to access information about drug uptake, metabolism, and response at a single-cell level.

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The impact of non-genetic heterogeneity on cancer cell death

Cited by 42 publications

References 113 publications

Drug persistence – From antibiotics to cancer therapies

Drug persistence – From antibiotics to cancer therapies

Large-Scale Analysis of Cell Death Phenotypic Heterogeneity

An Integrated Raman Spectroscopy and Mass Spectrometry Platform to Study Single-Cell Drug Uptake, Metabolism, and Effects

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