Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2− breast tumor cells

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(7)

Published: Feb. 7, 2024

The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor-positive, human epidermal growth factor 2 receptor-negative (ER+/HER2-) breast tumor cells. Despite the drug's success improving patient outcomes, a small percentage of cells continues to divide presence palbociclib-a phenomenon we refer as fractional resistance. It is critical understand cellular mechanisms underlying resistance because precise resistant tissue strong predictor clinical outcomes. Here, hypothesize that arises from cell-to-cell differences core regulators allow subset escape therapy. We used multiplex, single-cell imaging identify fractionally both cultured and primary samples resected patients. Resistant showed premature accumulation multiple G1 including E2F1, retinoblastoma protein, CDK2, well enhanced sensitivity pharmacological inhibition CDK2 activity. Using trajectory inference approaches, show how plasticity among gives rise alternate "paths" individual treatment. Understanding drivers plasticity, eliminate paths, could lead improved cancer therapies targeting improve

Language: Английский

---

Gene-level alignment of single-cell trajectories

Nature Methods, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 19, 2024

Language: Английский

---

Distinct gene regulatory dynamics drive skeletogenic cell fate convergence during vertebrate embryogenesis

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 4, 2025

Cell type repertoires have expanded extensively in metazoan animals, with some clade-specific cells being crucial to evolutionary success. A prime example are the skeletogenic of vertebrates. Depending on anatomical location, these originate from three different precursor lineages, yet they converge developmentally towards similar cellular phenotypes. Furthermore, their 'skeletogenic competency' arose at distinct timepoints, thus questioning what extent skeletal body parts rely truly homologous cell types. Here, we investigate how lineage-specific molecular properties integrated gene regulatory level, allow for fate convergence. Using single-cell functional genomics, find that transcription factor profiles inherited states and incorporated enhancer elements. This logic suggests regionalized types, rendering them amenable individualized selection, define adaptive morphologies biomaterial vertebrate skeleton.

Language: Английский

---

Distinct Gene Regulatory Dynamics Drive Skeletogenic Cell Fate Convergence During Vertebrate Embryogenesis

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

Published: March 29, 2024

Abstract Cell type repertoires have expanded extensively in metazoan animals, with some clade-specific cells being paramount to their evolutionary success. A prime example are the skeletogenic of vertebrates that form basis developing endoskeletons. Depending on anatomical location, these originate from three different embryonic precursor lineages – neural crest, somites, and lateral plate mesoderm yet they converge developmentally towards similar cellular phenotypes. Furthermore, gained ‘skeletogenic competency’ at distinct timepoints during vertebrate evolution, thus questioning what extent parts skeleton rely truly homologous cell types. Here, we investigate how lineage-specific molecular properties pools integrated gene regulatory level, allow for phenotypic convergence a fate. Using single-cell transcriptomics chromatin accessibility profiling along precursor-to-skeletogenic continuum, examine dynamics associated this fate convergence. We find transcription factor profiles inherited states, enhancer elements integrate inputs cis -regulatory execute core program. propose logic pools. Early skeletal body share only partial ‘deep homology’. This uncoupling may render them amenable individualized selection, help define morphologies biomaterial skeleton.

Language: Английский

---

Gene-level alignment of single cell trajectories

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 10, 2023

Abstract Single-cell data analysis can infer dynamic changes in cell populations, for example across time, space or response to perturbation. To compare these dynamics between two conditions, trajectory alignment via programming (DP) optimization is frequently used, but limited by assumptions such as a definite existence of match. Here we describe Genes2Genes , Bayesian information-theoretic DP framework aligning single-cell trajectories. overcomes current limitations and able capture sequential matches mismatches reference query at single gene resolution, highlighting distinct clusters genes with varying patterns expression dynamics. Across both real world simulated datasets, accurately captured different patterns, demonstrated its utility disease state analysis, revealed that T cells differentiated vitro matched an immature vivo while lacking associated TNFɑ signaling. This use case demonstrates precise pinpoint divergence from the system, thus guiding culture conditions.

Language: Английский

---

Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2- breast tumor cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 24, 2023

ABSTRACT The CDK4/6 inhibitor palbociclib blocks cell cycle progression in ER+/HER2- breast tumor cells. Although these drugs have significantly improved patient outcomes metastatic cancers, a small percentage of cells continues to divide the presence palbociclib—a phenomenon we refer as fractional resistance. It is critical understand cellular mechanisms underlying resistance because precise resistant tissue strong predictor clinical outcome. Here, hypothesize that arises from cell-to-cell differences core regulators allow subset escape therapy. We used multiplex, single-cell imaging identify fractionally both culture model cancer well live primary resected patient. found capable proliferating showed expected (e.g., CDK2, E2F1) and unexpected Cdt1, p21, cyclin B1) shifts regulators. Notably, models premature enrichment G1 E2F1 CDK2 protein and, unexpectedly, G2/M regulator B1 just before entry, suggesting may use noncanonical overcome inhibition. Using computational data integration trajectory inference approaches, show how plasticity gives rise alternate “paths” individual treatment. Understanding drivers plasticity, eliminate paths, could lead therapies targeting improve outcomes.

Language: Английский

---

The Lomb-Scargle periodogram-based differentially expressed gene detection along pseudotime

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

Published: Aug. 21, 2024

Abstract Motivation In recent years, single-cell RNA sequencing (scRNA-seq) has provided high-resolution snapshots of biological processes and contributed to the understanding cell dynamics. Trajectory inference potential provide a quantitative representation dynamics, several trajectory algorithms have been developed. However, downstream analysis inference, such as differentially expressed genes (DEG), remains challenging. Results this study, we introduce Lomb-Scargle (LS) periodogram-based algorithm for identifying DEGs associated with pseudotime in analysis. The is capable analyzing any inferred trajectory, including tree structures multiple branching points, leading diverse types. We validated approach using simulated data real datasets, our results showed that was superior when performing DEG on complex structured trajectories. Our will contribute gene characterization help gain deeper insights. Availability All code used proposed method can be found at https://github.com/hiuchi/LS . Contact [email protected] Supplementary information are available Journal Name online.

Language: Английский

---