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Article ; Online: Patterns of tumour transcriptional variability.

Ng, Raymond W S / Shaffer, Sydney M

2023 Volume 618, Issue 7965, Page(s) 464–465

MeSH term(s)	Humans ; Neoplasms ; Transcriptome
Language	English
Publishing date	2023-05-31
Publishing country	England
Document type	News
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/d41586-023-01744-0
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 9: Show issues
Zs.MO 244: Show issues

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Article: Breaking reflection symmetry: evolving long dynamical cycles in Boolean systems.

Ouellet, Mathieu / Kim, Jason Z / Guillaume, Harmange / Shaffer, Sydney M / Bassett, Lee C / Bassett, Dani S

New journal of physics

2024 Volume 26, Issue 2, Page(s) 23006

Abstract: In interacting dynamical systems, specific local interaction rules for system components give rise to diverse and complex global dynamics. Long dynamical cycles are a key feature of many natural interacting systems, especially in biology. Examples of ... ...

Abstract	In interacting dynamical systems, specific local interaction rules for system components give rise to diverse and complex global dynamics. Long dynamical cycles are a key feature of many natural interacting systems, especially in biology. Examples of dynamical cycles range from circadian rhythms regulating sleep to cell cycles regulating reproductive behavior. Despite the crucial role of cycles in nature, the properties of network structure that give rise to cycles still need to be better understood. Here, we use a Boolean interaction network model to study the relationships between network structure and cyclic dynamics. We identify particular structural motifs that support cycles, and other motifs that suppress them. More generally, we show that the presence of
Language	English
Publishing date	2024-02-06
Publishing country	England
Document type	Journal Article
ZDB-ID	1464444-7
ISSN	1367-2630
ISSN	1367-2630
DOI	10.1088/1367-2630/ad1bdd
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Article ; Online: Clonal differences underlie variable responses to sequential and prolonged treatment.

Schaff, Dylan L / Fasse, Aria J / White, Phoebe E / Vander Velde, Robert J / Shaffer, Sydney M

Cell systems

2024 Volume 15, Issue 3, Page(s) 213–226.e9

Abstract: Cancer cells exhibit dramatic differences in gene expression at the single-cell level, which can predict whether they become resistant to treatment. Treatment perpetuates this heterogeneity, resulting in a diversity of cell states among resistant clones. ...

Abstract	Cancer cells exhibit dramatic differences in gene expression at the single-cell level, which can predict whether they become resistant to treatment. Treatment perpetuates this heterogeneity, resulting in a diversity of cell states among resistant clones. However, it remains unclear whether these differences lead to distinct responses when another treatment is applied or the same treatment is continued. In this study, we combined single-cell RNA sequencing with barcoding to track resistant clones through prolonged and sequential treatments. We found that cells within the same clone have similar gene expression states after multiple rounds of treatment. Moreover, we demonstrated that individual clones have distinct and differing fates, including growth, survival, or death, when subjected to a second treatment or when the first treatment is continued. By identifying gene expression states that predict clone survival, this work provides a foundation for selecting optimal therapies that target the most aggressive resistant clones within a tumor. A record of this paper's transparent peer review process is included in the supplemental information.
MeSH term(s)	Humans ; Neoplasms/genetics ; Neoplasms/pathology ; Clone Cells/pathology ; Single-Cell Analysis/methods ; Exome Sequencing
Language	English
Publishing date	2024-02-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2854138-8
ISSN	2405-4720 ; 2405-4712
ISSN (online)	2405-4720
ISSN	2405-4712
DOI	10.1016/j.cels.2024.01.011
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Article ; Online: Integrating mutational and nonmutational mechanisms of acquired therapy resistance within the Darwinian paradigm.

Vander Velde, Robert / Shaffer, Sydney / Marusyk, Andriy

Trends in cancer

2022 Volume 8, Issue 6, Page(s) 456–466

Abstract: Mutational processes and nongenetic phenotypic state transitions represent distinct paradigms for understanding acquired resistance to targeted therapies. While ample empirical evidence supports both paradigms, they are typically viewed as mutually ... ...

Abstract	Mutational processes and nongenetic phenotypic state transitions represent distinct paradigms for understanding acquired resistance to targeted therapies. While ample empirical evidence supports both paradigms, they are typically viewed as mutually exclusive. However, a growing body of evidence points to the multifactorial nature of resistance, where resistant tumor cell phenotypes integrate the influence of multiple mutational and epigenetic changes. This leads to growing calls for a conceptual framework capable of incorporating the effects of genetic and nongenetic mechanisms. Here, we argue that the original Darwinian paradigm centered on the concept of natural selection, rather than its mutation-centric reinterpretation, might provide the optimal backbone for a much-needed synthesis.
MeSH term(s)	Drug Resistance, Neoplasm/genetics ; Epigenesis, Genetic ; Humans ; Mutation ; Neoplasms/drug therapy ; Phenotype ; Selection, Genetic
Language	English
Publishing date	2022-03-17
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2852626-0
ISSN	2405-8025 ; 2405-8033 ; 2405-8033
ISSN (online)	2405-8025 ; 2405-8033
ISSN	2405-8033
DOI	10.1016/j.trecan.2022.02.004
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Article: Clonal differences underlie variable responses to sequential and prolonged treatment.

Schaff, Dylan L / Fasse, Aria J / White, Phoebe E / Vander Velde, Robert J / Shaffer, Sydney M

bioRxiv : the preprint server for biology

2023

Abstract: Cancer cells exhibit dramatic differences in gene expression at the single-cell level which can predict whether they become resistant to treatment. Treatment perpetuates this heterogeneity, resulting in a diversity of cell states among resistant clones. ... ...

Abstract	Cancer cells exhibit dramatic differences in gene expression at the single-cell level which can predict whether they become resistant to treatment. Treatment perpetuates this heterogeneity, resulting in a diversity of cell states among resistant clones. However, it remains unclear whether these differences lead to distinct responses when another treatment is applied or the same treatment is continued. In this study, we combined single-cell RNA-sequencing with barcoding to track resistant clones through prolonged and sequential treatments. We found that cells within the same clone have similar gene expression states after multiple rounds of treatment. Moreover, we demonstrated that individual clones have distinct and differing fates, including growth, survival, or death, when subjected to a second treatment or when the first treatment is continued. By identifying gene expression states that predict clone survival, this work provides a foundation for selecting optimal therapies that target the most aggressive resistant clones within a tumor.
Language	English
Publishing date	2023-03-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.24.534152
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Article ; Online: E-cigarette use and respiratory symptoms in residents of the United States: A BRFSS report.

Varella, Marcia H / Andrade, Olyn A / Shaffer, Sydney M / Castro, Grettel / Rodriguez, Pura / Barengo, Noël C / Acuna, Juan M

PloS one

2022 Volume 17, Issue 12, Page(s) e0269760

Abstract: Purpose: E-cigarettes are the most common type of electronic nicotine delivery system in the United States. E-cigarettes contain numerous toxic compounds that has been shown to induce severe structural damage to the airways. The objective of this study ... ...

Abstract	Purpose: E-cigarettes are the most common type of electronic nicotine delivery system in the United States. E-cigarettes contain numerous toxic compounds that has been shown to induce severe structural damage to the airways. The objective of this study is to assess if there is an association between e-cigarette use and respiratory symptoms in adults in the US as reported in the BRFSS. Methods: We analyzed data from 18,079 adults, 18-44 years, who participated at the Behavioral Risk Factor Surveillance System (BRFSS) in the year 2017. E-cigarette smoking status was categorized as current everyday user, current some days user, former smoker, and never smoker. The frequency of any respiratory symptoms (cough, phlegm, or shortness of breath) was compared. Unadjusted and adjusted logistic regression analysis were used to calculate odds ratios (OR) and 95% confidence intervals (CI). Results: The BRFSS reported prevalence of smoking e-cigarettes was 6%. About 28% of the participants reported any of the respiratory symptoms assessed. The frequency of reported respiratory symptoms was highest among current some days e-cigarette users (45%). After adjusting for selected participant's demographic, socio-economic, and behavioral characteristics, and asthma and COPD status, the odds of reporting respiratory symptoms increased by 49% among those who use e-cigarettes some days (OR 1.49; 95% CI: 1.06-2.11), and by 29% among those who were former users (OR 1.29; 95% CI: 1.07-1.55) compared with those who never used e-cigarettes. No statistically significant association was found for those who used e-cigarettes every day (OR 1.41; 95% CI 0.96-2.08). Conclusion: E-cigarettes cannot be considered as a safe alternative to aid quitting use of combustible traditional cigarettes. Cohort studies may shed more evidence on the association between e-cigarette use and respiratory diseases.
MeSH term(s)	Adult ; United States/epidemiology ; Humans ; Vaping/adverse effects ; Vaping/epidemiology ; Electronic Nicotine Delivery Systems ; Behavioral Risk Factor Surveillance System ; Asthma ; Cough
Language	English
Publishing date	2022-12-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0269760
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Book ; Online: Excitation and inhibition imbalance affects dynamical complexity through symmetries

Ouellet, Mathieu / Kim, Jason Z. / Guillaume, Harmange / Shaffer, Sydney M. / Bassett, Lee C. / Bassett, Dani S.

2022

Abstract: From the perfect radial symmetries of radiolarian mineral skeletons to the broken symmetry of homochirality, the logic of Nature's regularities has fascinated scientists for centuries. Some of Nature's symmetries are clearly visible in morphology and ... ...

Abstract	From the perfect radial symmetries of radiolarian mineral skeletons to the broken symmetry of homochirality, the logic of Nature's regularities has fascinated scientists for centuries. Some of Nature's symmetries are clearly visible in morphology and physical structure, whereas others are hidden in the network of interactions among system components. Just as visible symmetries and asymmetries contribute to the system's beauty, might hidden symmetries contribute to the system's functional harmony? And if so, how? Here we demonstrate that the interaction networks of biological systems from cell signaling to cancer display a form of dynamical reflection symmetry that serves to expand their dynamical complexity. The expansion proceeds according to precise rules regarding the lengths of dynamical cycles, made possible by a peculiar imbalance between excitation and inhibition. To probe the conditions under which this reflection symmetry evolves, we use a multi-objective genetic algorithm to produce networks with long dynamical cycles. We find that local structural motifs that break the reflection symmetry are deleted in the evolutionary process, providing evidence for symmetry's causal role in dynamical complexity. Finally, we identify symmetries in real continuous-valued scRNA-seq data of gene expression in drug-resistant cancer cells. Broadly, our work reveals a class of hidden symmetries in biology, present in the network of interactions among system components, and it underscores their functional importance. Mathematically simple and computational inexpensive, our approach is applicable to the types of biological data commonly acquired in modern experiments. Comment: 21 pages, 12 figures
Keywords	Physics - Biological Physics ; Nonlinear Sciences - Chaotic Dynamics ; Nonlinear Sciences - Cellular Automata and Lattice Gases
Subject code	612
Publishing date	2022-02-23
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Clonal cell states link Barrett's esophagus and esophageal adenocarcinoma.

Gier, Rodrigo A / Hueros, Raúl A Reyes / Rong, Jiazhen / DeMarshall, Maureen / Karakasheva, Tatiana A / Muir, Amanda B / Falk, Gary W / Zhang, Nancy R / Shaffer, Sydney M

bioRxiv : the preprint server for biology

2023

Abstract: Barrett's esophagus is a common type of metaplasia and a precursor of esophageal adenocarcinoma. However, the cell states and lineage connections underlying the origin, maintenance, and progression of Barrett's esophagus have not been resolved in humans. ...

Abstract	Barrett's esophagus is a common type of metaplasia and a precursor of esophageal adenocarcinoma. However, the cell states and lineage connections underlying the origin, maintenance, and progression of Barrett's esophagus have not been resolved in humans. To address this, we performed single-cell lineage tracing and transcriptional profiling of patient cells isolated from metaplastic and healthy tissue. Our analysis revealed discrete lineages in Barrett's esophagus, normal esophagus, and gastric cardia. Transitional basal progenitor cells of the gastroesophageal junction were unexpectedly related to both esophagus and gastric cardia cells. Barrett's esophagus was polyclonal, with lineages that contained all progenitor and differentiated cell types. In contrast, precancerous dysplastic foci were initiated by the expansion of a single molecularly aberrant Barrett's esophagus clone. Together, these findings provide a comprehensive view of the cell dynamics of Barrett's esophagus, linking cell states along the full disease trajectory, from its origin to cancer.
Language	English
Publishing date	2023-02-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.26.525564
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Article ; Online: Variability within rare cell states enables multiple paths toward drug resistance.

Emert, Benjamin L / Cote, Christopher J / Torre, Eduardo A / Dardani, Ian P / Jiang, Connie L / Jain, Naveen / Shaffer, Sydney M / Raj, Arjun

Nature biotechnology

2021 Volume 39, Issue 7, Page(s) 865–876

Abstract: Molecular differences between individual cells can lead to dramatic differences in cell fate, such as death versus survival of cancer cells upon drug treatment. These originating differences remain largely hidden due to difficulties in determining ... ...

Abstract	Molecular differences between individual cells can lead to dramatic differences in cell fate, such as death versus survival of cancer cells upon drug treatment. These originating differences remain largely hidden due to difficulties in determining precisely what variable molecular features lead to which cellular fates. Thus, we developed Rewind, a methodology that combines genetic barcoding with RNA fluorescence in situ hybridization to directly capture rare cells that give rise to cellular behaviors of interest. Applying Rewind to BRAF
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cell Line ; Cell Survival/drug effects ; Drug Resistance, Neoplasm ; Extracellular Signal-Regulated MAP Kinases/genetics ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Integrin alpha3/genetics ; Integrin alpha3/metabolism ; Melanoma ; Phosphorylation ; Single-Cell Analysis ; Vemurafenib/pharmacology
Chemical Substances	Antineoplastic Agents ; ITGA3 protein, human ; Integrin alpha3 ; Vemurafenib (207SMY3FQT) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24)
Language	English
Publishing date	2021-02-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-021-00837-3
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Zs.A 2167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Disrupting cellular memory to overcome drug resistance.

Harmange, Guillaume / Hueros, Raúl A Reyes / Schaff, Dylan L / Emert, Benjamin / Saint-Antoine, Michael / Kim, Laura C / Niu, Zijian / Nellore, Shivani / Fane, Mitchell E / Alicea, Gretchen M / Weeraratna, Ashani T / Simon, M Celeste / Singh, Abhyudai / Shaffer, Sydney M

Nature communications

2023 Volume 14, Issue 1, Page(s) 7130

Abstract: Gene expression states persist for varying lengths of time at the single-cell level, a phenomenon known as gene expression memory. When cells switch states, losing memory of their prior state, this transition can occur in the absence of genetic changes. ... ...

Abstract	Gene expression states persist for varying lengths of time at the single-cell level, a phenomenon known as gene expression memory. When cells switch states, losing memory of their prior state, this transition can occur in the absence of genetic changes. However, we lack robust methods to find regulators of memory or track state switching. Here, we develop a lineage tracing-based technique to quantify memory and identify cells that switch states. Applied to melanoma cells without therapy, we quantify long-lived fluctuations in gene expression that are predictive of later resistance to targeted therapy. We also identify the PI3K and TGF-β pathways as state switching modulators. We propose a pretreatment model, first applying a PI3K inhibitor to modulate gene expression states, then applying targeted therapy, which leads to less resistance than targeted therapy alone. Together, we present a method for finding modulators of gene expression memory and their associated cell fates.
MeSH term(s)	Phosphatidylinositol 3-Kinases ; Cell Differentiation/genetics ; Drug Resistance, Neoplasm ; Transforming Growth Factor beta
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Transforming Growth Factor beta
Language	English
Publishing date	2023-11-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-41811-8
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