Increased heterogeneity in expression of genes associated with cancer progression and drug resistance DOI Creative Commons

Anwesha Bose,

Subhasis Datta, R. Mandal

et al.

Translational Oncology, Journal Year: 2024, Volume and Issue: 41, P. 101879 - 101879

Published: Jan. 22, 2024

Fluctuations in the number of regulatory molecules and differences timings molecular events can generate variation gene expression among genetically identical cells same environmental condition. This variation, termed as noise, create metabolic state cellular functions, leading to phenotypic heterogeneity. Expression noise heterogeneity have been recognized important contributors intra-tumor heterogeneity, associated with cancer growth, progression, therapy resistance. However, how changes progression actual patients has remained poorly explored. Such an analysis, through identification genes increasing provide valuable insights into generation could implications for understanding immune-suppression, drug tolerance In this work, we performed a genome-wide using single-cell RNA-seq data lung adenocarcinoma at different stages cancer. We identified 37 epithelial that showed trend many which were also EMT found several these was positively mitochondrial genes, suggesting role mitochondria addition, uncovered substantial sample-specific profiles personalized prognosis treatment.

Language: Английский

Live-seq enables temporal transcriptomic recording of single cells DOI Creative Commons
Wanze Chen, Orane Guillaume‐Gentil, Pernille Yde Rainer

et al.

Nature, Journal Year: 2022, Volume and Issue: 608(7924), P. 733 - 740

Published: Aug. 17, 2022

Single-cell transcriptomics (scRNA-seq) has greatly advanced our ability to characterize cellular heterogeneity1. However, scRNA-seq requires lysing cells, which impedes further molecular or functional analyses on the same cells. Here, we established Live-seq, a single-cell transcriptome profiling approach that preserves cell viability during RNA extraction using fluidic force microscopy2,3, thus allowing couple cell's ground-state its downstream phenotypic behaviour. To benchmark used growth, responses and whole-cell read-outs demonstrate Live-seq can accurately stratify diverse types states without inducing major perturbations. As proof of concept, show be directly map trajectory by sequentially transcriptomes individual macrophages before after lipopolysaccharide (LPS) stimulation, adipose stromal cells pre- post-differentiation. In addition, function as transcriptomic recorder preregistering were subsequently monitored time-lapse imaging LPS exposure. This enabled unsupervised, genome-wide ranking genes basis their affect macrophage response heterogeneity, revealing basal Nfkbia expression level cycle state important determinants, experimentally validated. Thus, address broad range biological questions transforming from an end-point temporal analysis approach.

Language: Английский

Citations

158
Exploring functional protein covariation across single cells using nPOP DOI Creative Commons
Andrew Leduc, R. Gray Huffman, Joshua Cantlon

et al.

Genome biology, Journal Year: 2022, Volume and Issue: 23(1)

Published: Dec. 16, 2022

Many biological processes, such as cell division cycle and drug resistance, are reflected in protein covariation across single cells. This can be quantified interpreted by single-cell mass spectrometry with sufficiently high throughput accuracy.

Language: Английский

Citations

104
Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells DOI
Yogesh Goyal, Gianna T. Busch, Maalavika Pillai

et al.

Nature, Journal Year: 2023, Volume and Issue: 620(7974), P. 651 - 659

Published: July 19, 2023

Language: Английский

Citations

102
Clonally heritable gene expression imparts a layer of diversity within cell types DOI Creative Commons
Jeff E. Mold, Martin H. Weissman, Michael Ratz

et al.

Cell Systems, Journal Year: 2024, Volume and Issue: 15(2), P. 149 - 165.e10

Published: Feb. 1, 2024

Cell types can be classified according to shared patterns of transcription. Non-genetic variability among individual cells the same type has been ascribed stochastic transcriptional bursting and transient cell states. Using high-coverage single-cell RNA profiling, we asked whether long-term, heritable differences in gene expression impart diversity within type. Studying clonal human lymphocytes mouse brain cells, uncovered a vast different clones vivo. We combined chromatin accessibility profiling on lymphocyte reveal thousands regulatory regions exhibiting interclonal variation, which could directly linked variation expression. Our findings identify source cellular diversity, may have important implications for how populations are shaped by selective processes development, aging, disease. A record this paper's transparent peer review process is included supplemental information.

Language: Английский

Citations

24
Unraveling non-genetic heterogeneity in cancer with dynamical models and computational tools DOI
Maalavika Pillai, Emilia Hojel, Mohit Kumar Jolly

et al.

Nature Computational Science, Journal Year: 2023, Volume and Issue: 3(4), P. 301 - 313

Published: April 24, 2023

Language: Английский

Citations

23
Disrupting cellular memory to overcome drug resistance DOI Creative Commons
Guillaume Harmange, Raúl A. Reyes Hueros, Dylan L. Schaff

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 6, 2023

Abstract Gene expression states persist for varying lengths of time at the single-cell level, a phenomenon known as gene memory. When cells switch states, losing memory their prior state, this transition can occur in absence genetic changes. However, we lack robust methods to find regulators or track state switching. Here, develop lineage tracing-based technique quantify and identify that states. Applied melanoma without therapy, long-lived fluctuations are predictive later resistance targeted therapy. We also PI3K TGF-β pathways switching modulators. propose pretreatment model, first applying inhibitor modulate then which leads less than therapy alone. Together, present method finding modulators associated cell fates.

Language: Английский

Citations

23
Cancer drug-tolerant persister cells: from biological questions to clinical opportunities DOI
Mariangela Russo,

Mengnuo Chen,

Elisa Mariella

et al.

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(10), P. 694 - 717

Published: Sept. 2, 2024

Language: Английский

Citations

15
Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency DOI Creative Commons
Moritz Jakab, Ki Hong Lee, Alexey Uvarovskii

et al.

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(5), P. 716 - 730

Published: Feb. 2, 2024

In metastasis, cancer cells travel around the circulation to colonize distant sites. Due rarity of these events, immediate fates metastasizing tumor (mTCs) are poorly understood while role endothelium as a dissemination interface remains elusive. Using newly developed combinatorial mTC enrichment approach, we provide transcriptional blueprint early colonization process. Following their arrest at metastatic site, mTCs were found either proliferate intravascularly or extravasate, thereby establishing latency. Endothelial-derived angiocrine Wnt factors drive this bifurcation, instructing follow extravasation-latency route. Surprisingly, responsiveness towards niche-derived was established epigenetic level, which predetermined cell behavior. Whereas hypomethylation enabled high activity leading latency, methylated exhibited low and proliferated intravascularly. Collectively data identify methylation status disseminated key regulator behavior in niche.

Language: Английский

Citations

13
Retrospective identification of cell-intrinsic factors that mark pluripotency potential in rare somatic cells DOI Creative Commons
Naveen K. Jain, Yogesh Goyal, Margaret C. Dunagin

et al.

Cell Systems, Journal Year: 2024, Volume and Issue: 15(2), P. 109 - 133.e10

Published: Feb. 1, 2024

Language: Английский

Citations

13
Reconstructing cell histories in space with image-readable base editor recording DOI Creative Commons
Duncan M. Chadly,

Kirsten L. Frieda,

Gui Chen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 4, 2024

Abstract Knowing the ancestral states and lineage relationships of individual cells could unravel dynamic programs underlying development. Engineering to actively record information within their own genomic DNA reveal these histories, but existing recording systems have limited capacity or disrupt spatial context. Here, we introduce baseMEMOIR , which combines base editing, sequential hybridization imaging, Bayesian inference allow reconstruction high-resolution cell trees state dynamics while preserving organization. BaseMEMOIR stochastically irreversibly edits engineered dinucleotides one three alternative image-readable states. By genomically integrating arrays editable dinucleotides, constructed an embryonic stem line with 792 bits recordable, memory, a 50-fold increase over art. Simulations showed that this memory size was sufficient for accurate deep trees. Experimentally, allowed precise 6 more generations in colonies. Further, it also quantitative transition rates, all from endpoint images. thus provides scalable framework reconstructing single histories spatially organized multicellular systems.

Language: Английский

Citations

9